Inhibitors of jun n-terminal kinase

ABSTRACT

The present disclosure provides inhibitors of c-Jun N-terminal kinases (JNK) having a structure according to the following formula: 
     
       
         
         
             
             
         
       
     
     or a salt or solvate thereof, wherein ring A, C a , C b , Z, R 5 , W and Cy are defined herein. The disclosure further provides pharmaceutical compositions including the compounds of the present disclosure and methods of making and using the compounds and compositions of the present disclosure, e.g., in the treatment and prevention of various disorders, such as Alzheimer&#39;s disease.

This application claims priority from U.S. Provisional PatentApplication No. 61/207,126 filed on Feb. 6, 2009, and from U.S.Provisional Patent Application No. 61/244,390 filed on Sep. 21, 2009,the disclosures each of which are incorporated herein by reference intheir entirety.

BACKGROUND OF THE DISCLOSURE

The present disclosure relates to inhibitors of c-Jun N-terminal kinases(JNKs). The disclosure also provides pharmaceutical compositionscomprising the inhibitors of the present disclosure and methods ofutilizing those compositions in the treatment of various disorders, suchas Alzheimer's disease.

Mammalian cells respond to extracellular stimuli by activating signalingcascades that are mediated by members of the mitogen-activated protein(MAP) kinase family, which include the extracellular signal regulatedkinases (ERKs), the p38 MAP kinases and the c-Jun N-terminal kinases(JNKs). MAP kinases (MAPKs) are serine/threonine kinases and areactivated by a variety of signals including growth factors, cytokines,UV radiation, and stress-inducing agents. MAPKs phosphorylate varioussubstrates including transcription factors, which in turn regulate theexpression of specific genes.

Members of the JNK family are activated by pro-inflammatory cytokines,such as tumor necrosis factor-alpha (TNF alpha) and interleukin-1 beta(IL-1 beta), as well as by environmental stress, including UVirradiation, hypoxia, and osmotic shock (see, e.g., Minden et al.,Biochemica et Biophysica Acta 1997, 1333:F85-F104). Three distinct JNKgenes, jnk1, jnk2 and jnk3 were identified and at least ten differentsplicing isoforms exist in mammalian cells (see, e.g., Gupta et al.,EMBO J. 1996, 15:2760-2770).

Down-stream substrates of JNKs include transcription factors c-Jun,ATF-2, Elk1, p53 and a cell death domain protein (DENN) (see. e.g.,Zhang et al. Proc. Natl. Acad. Sci. USA 1998, 95:2586-2591). Each JNKisoform binds to these substrates with different affinities, suggestinga regulation of signaling pathways by substrate specificity in vivo(Gupta el al., supra).

JNKs have been implicated in mediating a number of physiologicalresponses and disorders including cellular-response to cancer,thrombin-induced platelet aggregation, immunodeficiency disorders,autoimmune diseases, cell death, allergies, osteoporosis and heartdisease. The therapeutic targets related to activation of the JNKpathway include chronic myelogenous leukemia (CML), rheumatoidarthritis, asthma, osteoarthritis, ischemia, various cancers andneurodegenerative diseases.

Several reports have detailed the importance of JNK activationassociated with liver disease or episodes of hepatic ischemia (see,e.g., Nat. Genet. 1999, 21:326-329; FEBS Lett. 1997, 420:201-204; J.Clin. Invest. 1998, 102:1942-1950; Hepatology 1998, 28:1022-1030). Arole for JNK in cardiovascular disease such as myocardial infarction orcongestive heart failure has also been reported (see, e.g., Circ. Res.1998, 83:167-178; Circulation 1998, 97:1731 -7). The JNK cascade alsoplays a role in T-cell activation, including activation of the IL-2promoter (see, e.g., J. Immunol. 1999, 162:3176-87; Eur. J. Immunol.1998, 28:3867-77; J. Exp. Med. 1997). A role for JNK activation invarious forms of cancer has also been established. For example,constitutively activated JNK is associated with HTLV-1 mediatedtumorigenesis (Oncogene 1996, 13:135-42). JNK may play a role inKaposi's sarcoma (KS) because it is thought that the proliferativeeffects of bFGF and OSM on KS cells are mediated by their activation ofthe JNK signaling pathway (see e.g., J. Clin. Invest. 1997,99:1798-804). Other proliferative effects of certain cytokinesimplicated in KS proliferation, such as vascular endothelial growthfactor (VEGF), IL-6 and TNF alpha, may also be mediated by JNK. Inaddition, regulation of the c-jun gene in p210 BCR-ABL transformed cellscorresponds with activity of JNK, suggesting a role for JNK inhibitorsin the treatment for chronic myelogenous leukemia (CML) (sec, e.g.,Blood 1998, 92-2450-60).

While JNK1 and JNK2 are widely expressed in a variety of tissues, JNK3is selectively expressed in the brain and, to a lesser extent, in theheart and testis (see, e.g., Gupta et al., supra; Mohit et al., Neuron1995, 14:67-78; Martin et al., Brain Res. Mol. Brain. Res. 1996,35:47-57). JNK3 has been linked to neuronal apoptosis induced by kainicacid, indicating a role of JNK in the pathogenesis of glutamateneurotoxicity. In the adult human brain, JNK3 expression is localized toa subpopulation of pyramidal neurons in the CA1, CA4 and subiculumregions of the hippocampus and layers 3 and 5 of the neocortex (Mohit elal., supra). The CA1 neurons of patients with acute hypoxia showedstrong nuclear JNK3-immunoreactivity compared to minimal, diffusecytoplasmic staining of the hippocampal neurons from brain tissues ofnormal patients (Zhang et et al., supra). Thus, JNK3 appears to beinvolved in hypoxic and ischemic damage of CA1 neurons in thehippocampus.

Disruption of the JNK3 gene caused resistance of mice to the excitotoxicglutamate receptor agonist kainic acid, including the effects on seizureactivity, AP-1 transcriptional activity and apoptosis of hippocampalneurons, indicating that the JNK3 signaling pathway is a criticalcomponent in the pathogenesis of glutamate neurotoxicity (Yang et al.,Nature 1997, 389:865-870).

In addition, JNK3 co-localizes immunochemically with neurons vulnerablein Alzheimer's disease (Mohit el al., supra). Based on these findings,JNK signalling, especially that of JNK3, has been implicated in theareas of apoptosis-driven neurodegenerative diseases such as Alzheimer'sDisease, Parkinson's Disease, amyotrophic lateral sclerosis (ALS),epilepsy, seizures, Huntington's Disease, traumatic brain injuries, aswell as ischemic and hemorrhaging stroke.

Drug molecules that inhibit MAPKs, such as p38 are known (see, e.g., WO98/27098 and WO 95/31451). However, inhibitors that are selective forJNKs versus other members of the MAPK family are rare (see, e.g., U.S.Patent Application Publication 20080033022). There is an unmet medicalneed for the development of potent, JNK specific inhibitors that areuseful in treating the various conditions associated with JNKactivation.

SUMMARY OF THE DISCLOSURE

In various aspects, the present disclosure provides for a compoundhaving a structure according to Formula (I):

or a salt or solvate thereof, wherein ring A is 5-membered heteroarylcomprising a sulfur atom, wherein the heteroaryl is optionallysubstituted with 1 or 2 substituents independently chosen from alkyl,alkenyl, alkynyl, haloalkyl, heteroalkyl, C₃-C₁₀-cycloalkyl, 3- to8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN,halogen, OR¹², SR¹², NR¹²R¹³, C(O)R¹⁴, C(O)NR¹²R¹³, OC(O)NR¹²R¹³,C(O)OR¹², NR¹⁵C(O)R¹⁴, NR¹⁵C(O)OR¹², NR¹⁵C(O)NR¹²R¹³, NR¹⁵C(S)NR¹²R¹³,NR¹⁵S(O)₂R¹⁴, S(O)₂NR¹²R¹³, S(O)R¹⁴and S(O)₂R¹⁴, wherein R¹², R¹³ andR¹⁵ are independently chosen from H, acyl, C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, or R¹² and R¹³, together with thenitrogen atom to which they are bound form a 5- to 7-memberedheterocyclic ring; and R¹⁴ is chosen from acyl, C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl; C^(a) and C^(b) arecarbon atoms, which are adjacent to each other and are part of ring A; Zis 5- or 6-membered heteroaryl, with the proviso that (i) when ring A isthiophene, then Z is not a heteroaryl chosen from benzoimidazole,thiazole, and benzothiazole; (ii) when ring A is thiazole, then Z is notbenzoimidazole; (iii) when ring A is thiophene, then Z is notsubstituted oxadiazole; and (iv) when ring A is thiophene, then Z is notpyrimidinone; R⁵ is chosen from H, acyl, C₁-C₆ alkyl, and C₃-C₆cycloalkyl; W is chosen from C₁-C₄ alkylene, wherein the alkylene isoptionally substituted with 1-4 substituents independently chosen fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, C₃-C₆-cycloalkyl, 3- to8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN,halogen, OR⁴², SR⁴², NR⁴²R⁴³, C(O)R⁴⁴, C(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³,C(O)OR⁴², NR⁴⁵C(O)R⁴⁴, NR⁴⁵C(O)OR⁴², NR⁴⁵C(O)NR⁴²R⁴³, NR⁴⁵C(S)NR⁴²R⁴³,NR⁴⁵S(O)₂R⁴⁴, S(O)₂NR⁴²R⁴³, S(O)R⁴⁴, and S(O)₂R⁴⁴, and R⁴², R⁴³ andR⁴⁵are members independently chosen from H, acyl, C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl, wherein R⁴²and R⁴³,together with the nitrogen atom to which they are bound are optionallyjoined to form a 5- to 7-membered heterocyclic ring; and R⁴⁴ isindependently chosen from acyl, C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl; Cy is chosen from cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl,heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1-6substituents independently chosen from substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, haloalkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, CN, halogen, OR⁵², SR⁵²,NR⁵²R⁵³, C(O)R⁵⁴, C(O)NR⁵²R⁵³, OC(O)NR⁵²R⁵³, C(O)OR⁵², NR⁵⁵C(O)R⁵⁴,NR⁵⁵C(O)OR⁵², NR⁵⁵C(O)OR⁵², NR⁵⁵C(O)NR⁵²R⁵³, NR⁵⁵C(S)NR⁵²R⁵³,NR⁵⁵S(O)₂R⁵⁴, S(O)₂NR⁵²R⁵³, S(O)R⁵⁴ and S(O)₂R⁵⁴, wherein R⁵², R⁵³ andR⁵⁵ are independently chosen from H, acyl C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, wherein R⁵²and R⁵³, together with thenitrogen atom to which they are bound are optionally joined to form a 5-to 7-membered heterocyclic ring; and R⁵⁴ is independently chosen fromacyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl. Thepresent disclosure further provides for a pharmaceutical compositioncomprising a compound according to Formula (I) and a pharmaceuticallyacceptable carrier.

The present disclosure also provides for compound having a structureaccording to Formula (VIII):

or a tautomer, mixture of tautomers, salt or solvate thereof, whereinring A is 5- or 6-membered heteroaryl, wherein the heteroaryl isoptionally substituted with 1-3 substituents independently chosen fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, C₃-C₁₀-cycloalkyl, 3-to 8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN,halogen, OR¹², SR¹², NR¹²R¹³, C(O)R¹⁴, C(O)NR¹²R¹³, OC(O)NR¹²R¹³,C(O)OR¹², NR¹⁵C(O)R¹⁴, NR¹⁵C(O)OR¹², NR¹⁵C(O)NR¹²R¹³, NR¹⁵C(S)NR¹²R¹³,NR¹⁵S(O)₂R¹⁴, S(O)₂R¹²R¹³, S(O)R¹⁴ and S(O)₂R¹⁴, wherein R¹², R¹³ andR¹⁵ are independently chosen form H, acyl, C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, or R¹²and R¹³, together with thenitrogen atom to which they are bound form a 5- to 7-memberedheterocyclic ring; and R¹⁴ is chosen from acyl, C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl; C^(a) and C^(b) arecarbon atoms, which are adjacent to each other and, which are part ofring A; R⁴ is chosen from H, independently chosen from H, C₁-C₄ alkyl,C₁-C₄ alkenyl, C₁-C₄ alkynyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, 3- to6-membered heterocycloalkyl, aryl, and 5- or 6-membered heteroaryl, CN,halogen, OR¹⁷, SR¹⁷ and NR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are independentlychosen from H, acyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5-to 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3- to 8-memberedheterocycloalkyl, or R¹⁷ or R¹⁸, together with the nitrogen atom towhich they are bound form a 5- to 7-membered heterocyclic ring; R⁵ ischosen from H, acyl, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl; W is chosen fromC₁-C₄ alkylene, wherein the alkylene is optionally substituted with from1 to 4 substituents chosen from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl, C₃-C₆-cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl5- or 6-membered heteroaryl, CN, halogen, OR⁴², SR⁴², NR⁴²R⁴³, C(O)R⁴⁴,C(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³, C(O)OR⁴², NR⁴⁵C(O)R⁴⁴, NR⁴⁵C(O)OR⁴²,NR⁴⁵C(O)NR⁴²R⁴³, NR⁴⁵C(S)NR⁴²R⁴³, NR⁴⁵S(O)₂R⁴⁴, S(O)₂NR⁴²R⁴³, S(O)R⁴⁴,and S(O)₂R⁴⁴, wherein R⁴², R⁴³ and R⁴⁵ are independently chosen from H,acyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl,wherein R⁴² and R⁴³, together with the nitrogen atom to which they arebound are optionally joined to form a 5- to 7-membered heterocyclicring; and R⁴⁴ is independently chosen from acyl, C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl; Cy is chosen fromcycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein thecycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionallysubstituted with 1-6 substituents independently chosen from substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, haloalkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, CN,halogen, OR⁵², SR⁵², NR⁵²R⁵³, C(O)R⁵⁴, C(O)NR⁵²R⁵³, OC(O)NR⁵²R⁵³,C(O)OR⁵², NR⁵⁵C(O)R⁵⁴, NR⁵⁵C(O)OR⁵², NR⁵⁵C(O)OR⁵², NR⁵⁵C(O)NR⁵²R⁵³,NR⁵⁵C(S)NR⁵²R⁵³, NR⁵⁵S(O)₂R⁵⁴, S(O)₂NR⁵²R⁵³, S(O)R⁵⁴ and S(O)₂R⁵⁴,wherein R⁵², R⁵³ and R⁵⁵ are independently chosen from H, acylC₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl,wherein R⁵²and R⁵³, together with the nitrogen atom to which they arebound are optionally joined to form a 5- to 7-membered heterocyclicring; and R⁵⁴ is independently chosen from acyl, C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl. The present disclosurefurther provides for a pharmaceutical composition comprising a compoundaccording to Formula (VIII) and a pharmaceutically acceptable carrier.

The present disclosure further provides for a compound having astructure according to Formula (X) or Formula (XI):

or a salt or solvate thereof, wherein X¹ is chosen from N and CR^(2a);R² and R^(2a) are independently chosen from H, C₁-C₄-alkyl,C₁-C₄-alkenyl, C₁-C₄-alkynyl, C₁-C₄-haloalkyl, 2- to 4-memberedheteroalkyl, C₃-C₆-cycloalkyl, 3- to 6-membered heterocycloalkyl, CN,and halogen; R¹⁰ and R¹¹ are independently chosen from H, C₁-C₆-alkyl,C₁-C₆-alkenyl, C₁-C₆-alkynyl, C₁-C₆-haloalkyl, 2- to 6-memberedheteroalkyl, C₃-C₆-cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl,5- to 6-membered heteroaryl, CN, halogen, OR⁴², SR⁴², NR⁴²R⁴³, C(O)R⁴⁴,C(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³, C(O)OR⁴², NR⁴⁵C(O)R⁴⁴, NR⁴⁵C(O)OR⁴²,NR⁴⁵C(O)NR⁴²R⁴³, NR⁴⁵C(S)NR⁴²R⁴³, NR⁴⁵S(O)₂R⁴⁴, S(O)₂NR⁴²R⁴³, S(O)R⁴⁴and S(O)₂R⁴⁴, wherein R⁴², R⁴³ and R⁴⁵ are independently chosen from H,acyl C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl, orR⁴² and R⁴³, together with the nitrogen atom to which they are boundform a 5- to 7-membered heterocyclic ring; and R⁴⁴ is chosen from acyl,C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl, R⁵is chosen from H and substituted or unsubstituted C₁-C₆ alkyl; Cy ischosen from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, whereinthe cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionallysubstituted with from 1 to 6 substituents independently chosen fromC₁-C₆-alkyl, C₁-C₆-alkenyl, C₁-C₆-alkynyl, C₁-C₆haloalkyl, 2- to6-membered heteroalkyl, C₃-C₁₂-cycloalkyl, 3- to 8-memberedheterocycloalkyl, aryl, 5- to 6-membered heteroaryl, CN, halogen, OR⁵²,SR⁵², NR⁵²R⁵³, C(O)R⁵⁴, C(O)NR⁵²R⁵³, OC(O)NR⁵²R⁵³, C(O)OR⁵²,NR⁵⁵C(O)R⁵⁴, NR⁵⁵C(O)OR⁵², NR⁵⁵C(O)NR⁵²R⁵³, NR⁵⁵C(S)NR⁵²R⁵³,NR⁵⁵S(O)₂R⁵⁴, S(O)₂NR⁵²R⁵³, S(O)R⁵⁴ and S(O)₂R⁵⁴, wherein R⁵², R⁵³ andR⁵⁵ are independently chosen from H, acyl C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, wherein R⁵² and R⁵³, together with thenitrogen atom to which they are bound are optionally joined to form a 5-to 7-membered heterocyclic ring; and R⁵⁴ is independently chosen fromacyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl; andZ is chosen from:

wherein Y⁵ is chosen from O, S and NR³, and wherein R³ is chosen from H,alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, 3- to 8-memberedheterocycloalkyl, aryl, and 5- or 6-membered heteroaryl; and R⁴, R^(4a)and R¹⁶ are independently chosen from H, alkyl, alkenyl, alkynyl,haloalkyl, cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, 5- to6-membered heteroaryl, CN, halogen, OR¹⁷, SR¹⁷, NR¹⁷R¹⁸, wherein R¹⁷ andR¹⁸ are independently chosen from H, acyl, C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, or R¹⁷ and R¹⁸, together with thenitrogen atom to which they are bound form a 5- to 7-memberedheterocyclic ring, or two of R⁴, R^(4a) and R³, together with the atomsto which they are attached, form a 5- to 7-membered ring, or adjacentR¹⁶ groups, together with the carbon atoms to which they are attached,form a 5- to 7-membered ring; n is an integer chosen from 0 to 4; and mis an integer chosen from 0 to 3. The present disclosure furtherprovides for a pharmaceutical composition comprising a compoundaccording to Formula (X) or (XI) and a pharmaceutically acceptablecarrier.

The present disclosure also provides for a method of treating aneurodegenerative disease comprising administering to a mammaliansubject in need thereof a pharmaceutically effective amount of acompound having a structure according to Formula (I):

or a salt or solvate thereof, wherein ring A is 5-membered heteroarylcomprising a sulfur atom, wherein the heteroaryl is optionallysubstituted with 1 or 2 substituents independently chosen from alkyl,alkenyl, alkynyl, haloalkyl, heteroalkyl, C₃-C₁₀-cycloalkyl, 3- to8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN,halogen, OR¹², SR¹², NR¹²R¹³, C(O)R¹⁴, C(O)NR¹²R¹³, OC(O)NR¹²R¹³,C(O)OR¹², NR¹⁵C(O)R¹⁴, NR¹⁵C(O)OR¹², NR¹⁵C(S)NR¹²R¹³, NR¹⁵S(O)₂R¹⁴,S(O)₂NR¹²R¹³, S(O)R¹⁴ and S(O)₂R¹⁴, wherein R¹², R¹³ and R¹⁵ areindependently chosen from H, acyl C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, or R¹² and R¹³, together with thenitrogen atom to which they are bound form a 5- to 7-memberedheterocyclic ring; and R¹⁴ is chosen from acyl, C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl; C^(a) and C^(b) arecarbon atoms, which are adjacent to each other and are part of ring A; Zis 5- or 6-membered heteroaryl, R⁵ is chosen from H, acyl, C₁-C₆ alkyl,and C₃-C₆ cycloalkyl; W is chosen from C₁-C₄ alkylene, wherein thealkylene is optionally substituted with 1-4 substituents independentlychosen from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl,C₃-C₆-cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, 5- or6-membered heteroaryl, CN, halogen, OR⁴², SR⁴², NR⁴²R⁴³, C(O)R⁴⁴,C(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³, C(O)OR⁴², NR⁴⁵C(O)R⁴⁴, NR⁴⁵C(O)OR⁴²,NR⁴⁵C(O)NR⁴²R⁴³, NR⁴⁵C(S)NR⁴²R⁴³, NR⁴⁵S(O)₂R⁴⁴, S(O)₂NR⁴²R⁴³, S(O)R⁴⁴,and S(O)₂R⁴⁴, and R⁴², R⁴³ and R⁴⁵are members independently chosen fromH, acyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or6-membered heteroaryl, C₃-C₈ cycloalkyl and 3- to 8-memberedheterocycloalkyl, wherein R⁴² and R⁴³, together with the nitrogen atomto which they are bound are optionally joined to form a 5- to 7-memberedheterocyclic ring; and R⁴⁴ is independently chosen from acyl,C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl; Cyis chosen from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl isoptionally substituted with 1-6 substituents independently chosen fromsubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, haloalkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, CN,halogen, OR⁵², SR⁵², NR⁵²R⁵³, C(O)R⁵⁴, C(O)NR⁵²R⁵³, OC(O)NR⁵²R⁵³,C(O)OR⁵², NR⁵⁵C(O)R⁵⁴, NR⁵⁵C(O)OR⁵², NR⁵⁵C(O)NR⁵²R⁵³, NR⁵⁵C(S)NR⁵²R⁵³,NR⁵⁵S(O)₂R⁵⁴, S(O)₂NR⁵²R⁵³, S(O)R⁵⁴ and S(O)₂R⁵⁴, wherein R⁵², R⁵³ andR⁵⁵ are independently chosen from H, acyl C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, wherein R⁵² and R⁵³, together with thenitrogen atom to which they are bound are optionally joined to form a 5-to 7-membered heterocyclic ring; and R⁵⁴ is independently chosen fromacyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl.

The present disclosure also provides for a method of reducing p-cjunconcentration in brain tissue of a subject in need thereof, the methodcomprising administering to the subject a compound having a structureaccording to Formula (I):

or a salt or solvate thereof, wherein ring A is 5-membered heteroarylcomprising a sulfur atom, wherein the heteroaryl is optionallysubstituted with 1 or 2 substituents independently chosen from alkyl,alkenyl, alkynyl, haloalkyl, heteroalkyl, C₃-C₁₀-cycloalkyl, 3- to8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN,halogen, OR¹², SR¹², NR¹²R¹³, C(O)R¹⁴, C(O)NR¹²R¹³, OC(O)NR¹²R¹³,C(O)OR¹², NR¹⁵C(O)R¹⁴, NR¹⁵C(O)OR¹², NR¹⁵C(O)NR¹²R¹³, NR¹⁵C(S)NR¹²R¹³,NR¹⁵S(O)₂R¹⁴, S(O)₂NR¹²R¹³, S(O)R¹⁴ and S(O)₂R¹⁴, wherein R¹², R¹³ andR¹⁵ are independently chosen from H, acyl C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, wherein R¹² and R¹³, together with thenitrogen atom to which they are bound are optionally joined to form a 5-to 7-membered heterocyclic ring; and R¹⁴ is independently chosen fromacyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl;C^(a) and C^(b) are carbon atoms, which are adjacent to each other andare part of ring A; Z is 5- or 6-membered heteroaryl; R⁵ is chosen fromH, acyl, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl; W is chosen from C₁-C₄alkylene, wherein the alkylene is optionally substituted with 1-4substituents independently chosen from alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl, C₃-C₆-cycloalkyl, 3- to 8-memberedheterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR⁴²,SR⁴², NR⁴²R⁴³, C(O)R⁴⁴, C(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³, C(O)OR⁴²,NR⁴⁵C(O)R⁴⁴, NR⁴⁵C(O)OR⁴², NR⁴⁵C(O)NR⁴²R⁴³, NR⁴⁵C(S)NR⁴²R⁴³,NR⁴⁵S(O)₂R⁴⁴, S(O)₂NR⁴²R⁴³, S(O)R⁴⁴, and S(O)₂R⁴⁴, wherein R⁴², R⁴³ andR⁴⁵ are members independently chosen from H, acyl C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl, wherein R⁴² and R⁴³,together with the nitrogen atom to which they are bound are optionallyjoined to form a 5- to 7-membered heterocyclic ring; and R⁴⁴ isindependently chosen from acyl, C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- to 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl; Cy is chosen from cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl,heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1-6substituents independently chosen from substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, haloalkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, CN, halogen, OR⁵², SR⁵²,NR⁵²R⁵³, C(O)R⁵⁴, C(O)NR⁵²R⁵³, OC(O)NR⁵²R⁵³, C(O)OR⁵², NR⁵⁵C(O)R⁵⁴,NR⁵⁵C(O)OR⁵², NR⁵⁵C(O)NR⁵²R⁵³, NR⁵⁵C(S)NR⁵²R⁵³, NR⁵⁵S(O)₂R⁵⁴,S(O)₂NR⁵²R⁵³, S(O)R⁵⁴ and S(O)₂R⁵⁴, wherein R⁵², R⁵³ and R⁵⁵ areindependently chosen from H, acyl C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, wherein R⁵² and R⁵³, together with thenitrogen atom to which they are bound are optionally joined to form a 5-to 7-membered heterocyclic ring; and R⁵⁴ is independently chosen fromacyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl.

In addition, the present disclosure provides for use of a compound in anin vitro assay measuring kinase activity, said compound having astructure according to Formula (I):

or a salt or solvate thereof, wherein ring A is 5-membered heteroarylcomprising a sulfur atom, wherein the heteroaryl is optionallysubstituted with 1 or 2 substituents independently chosen from alkyl,alkenyl, alkynyl, haloalkyl, heteroalkyl, C₃-C₁₀-cycloalkyl, 3- to8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN,halogen, OR¹², SR¹², NR¹²R¹³, C(O)R¹⁴, C(O)NR¹²R¹³, OC(O)NR¹²R¹³,C(O)OR¹², NR¹⁵C(O)R¹⁴, NR¹⁵C(O)OR¹², NR¹⁵C(O)NR¹²R¹³, NR¹⁵C(S)NR¹²R¹³,NR¹⁵S(O)₂R¹⁴, S(O)₂NR¹²R¹³, S(O)R¹⁴ and S(O)₂R¹⁴, wherein R¹², R¹³ andR¹⁵ are independently chosen from H, acyl C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, wherein R¹² and R¹³, together with thenitrogen atom to which they are bound are optionally joined to form a 5-to 7-membered heterocyclic ring; and R¹⁴ is independently chosen fromacyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl;C^(a) and C^(b) are carbon atoms, which are adjacent to each other andare part of ring A; Z is 5- or 6-membered heteroaryl; R⁵ is chosen fromH, acyl, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl; W is chosen from C₁-C₄alkylene, wherein the alkylene is optionally substituted with 1-4substituents independently chosen from alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl, C₃-C₆-cycloalkyl, 3- to 8-memberedheterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR⁴²,SR⁴², NR⁴²R⁴³, C(O)R⁴⁴, C(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³, C(O)OR⁴²,NR⁴⁵C(O)R⁴⁴, NR⁴⁵C(O)OR⁴², NR⁴⁵C(O)NR⁴²R⁴³, NR⁴⁵C(S)NR⁴²R⁴³,NR⁴⁵S(O)₂R⁴⁴, S(O)₂NR⁴²R⁴³, S(O)R⁴⁴, and S(O)₂R⁴⁴, wherein R⁴², R⁴³ andR⁴⁵ are members independently chosen from H, acyl C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl, wherein R⁴² and R⁴³,together with the nitrogen atom to which they are bound are optionallyjoined to form a 5- to 7-membered heterocyclic ring; and R⁴⁴ isindependently chosen from acyl, C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- to 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl; Cy is chosen from cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl,heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1-6substituents independently chosen from substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, haloalkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, CN, halogen, OR⁵², SR⁵²,NR⁵²R⁵³, C(O)R⁵⁴, C(O)NR⁵²R⁵³, OC(O)NR⁵²R⁵³, C(O)OR⁵², NR⁵⁵C(O)R⁵⁴,NR⁵⁵C(O)OR⁵², NR⁵⁵C(O)NR⁵²R⁵³, NR⁵⁵C(S)NR⁵²R⁵³, NR⁵⁵S(O)₂R⁵⁴,S(O)₂NR⁵²R⁵³, S(O)R⁵⁴ and S(O)₂R⁵⁴, wherein R⁵², R⁵³ and R⁵⁵ areindependently chosen from H, acyl C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, wherein R⁵² and R⁵³, together with thenitrogen atom to which they are bound are optionally joined to form a 5-to 7-membered heterocyclic ring; and R⁵⁴ is independently chosen fromacyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl.

The present disclosure also provides for a use of a compound in an invivo assay measuring kinase activity, said compound having a structureaccording to Formula (I):

or a salt or solvate thereof, wherein ring A is 5-membered heteroarylcomprising a sulfur atom, wherein the heteroaryl is optionallysubstituted with 1 or 2 substituents independently chosen from alkyl,alkenyl, alkynyl, haloalkyl, heteroalkyl, C₃-C₁₀-cycloalkyl, 3- to8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN,halogen, OR¹², SR¹², NR¹²R¹³, C(O)R¹⁴, C(O)NR¹²R¹³, OC(O)NR¹²R¹³,C(O)OR¹², NR¹⁵C(O)R¹⁴, NR¹⁵C(O)OR¹², NR¹⁵C(O)NR¹²R¹³, NR¹⁵C(S)NR¹²R¹³,NR¹⁵S(O)₂R¹⁴, S(O)₂NR¹²R¹³, S(O)R¹⁴ and S(O)₂R¹⁴, wherein R¹², R¹³ andR¹⁵ are independently chosen from H, acyl C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, wherein R¹² and R¹³, together with thenitrogen atom to which they are bound are optionally joined to form a 5-to 7-membered heterocyclic ring; and R¹⁴ is chosen from acyl,C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl;C^(a) and C^(b) are carbon atoms, which are adjacent to each other andare part of ring A; Z is 5- or 6-membered heteroaryl; R⁵ is chosen fromH, acyl, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl; W is chosen from C₁-C₄alkylene, wherein the alkylene is optionally substituted with 1-4substituents independently chosen from alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl, C₃-C₆-cycloalkyl, 3- to 8-memberedheterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR⁴²,SR⁴², NR⁴²R⁴³, C(O)R⁴⁴, C(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³, C(O)OR⁴²,NR⁴⁵C(O)R⁴⁴, NR⁴⁵C(O)OR⁴², NR⁴⁵C(O)NR⁴²R⁴³, NR⁴⁵C(S)NR⁴²R⁴³,NR⁴⁵S(O)₂R⁴⁴, S(O)₂NR⁴²R⁴³, S(O)R⁴⁴, and S(O)₂R⁴⁴, wherein R⁴², R⁴³ andR⁴⁵ are members independently chosen from H, acyl C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl, wherein R⁴² and R⁴³,together with the nitrogen atom to which they are bound are optionallyjoined to form a 5- to 7-membered heterocyclic ring; and R⁴⁴ isindependently chosen from acyl, C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- to 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl; Cy is chosen from cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl,heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1-6substituents independently chosen from substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, haloalkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, CN, halogen, OR⁵², SR⁵²,NR⁵²R⁵³, C(O)R⁵⁴, C(O)NR⁵²R⁵³, OC(O)NR⁵²R⁵³, C(O)OR⁵², NR⁵⁵C(O)R⁵⁴,NR⁵⁵C(O)OR⁵², NR⁵⁵C(O)NR⁵²R⁵³, NR⁵⁵C(S)NR⁵²R⁵³, NR⁵⁵S(O)₂R⁵⁴,S(O)₂NR⁵²R⁵³, S(O)R⁵⁴ and S(O)₂R⁵⁴, wherein R⁵², R⁵³ and R⁵⁵ areindependently chosen from H, acyl C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, wherein R⁵² and R⁵³, together with thenitrogen atom to which they are bound are optionally joined to form a 5-to 7-membered heterocyclic ring; and R⁵⁴ is independently chosen fromacyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl.

The present disclosure further provides for an in vitro method formeasuring phosphorylated kinase substrate comprising: (i) creating amixture comprising a kinase and a compound having a structure accordingto Formula (I):

or a salt or solvate thereof, wherein ring A is 5-membered heteroarylcomprising a sulfur atom, wherein the heteroaryl is optionallysubstituted with 1 or 2 substituents independently chosen from alkyl,alkenyl, alkynyl, haloalkyl, heteroalkyl, C₃-C₁₀-cycloalkyl, 3- to8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN,halogen, OR¹², SR¹², NR¹²R¹³, C(O)R¹⁴, C(O)NR¹²R¹³, OC(O)NR¹²R¹³,C(O)OR¹², NR¹⁵C(O)R¹⁴, NR¹⁵C(O)OR¹², NR¹⁵C(O)NR¹²R¹³, NR¹⁵C(S)NR¹²R¹³,NR¹⁵S(O)₂R¹⁴, S(O)₂NR¹²R¹³, S(O)R¹⁴ and S(O)₂R¹⁴, wherein R¹², R¹³ andR¹⁵ are independently chosen from H, acyl C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, wherein R¹² and R¹³, together with thenitrogen atom to which they are bound are optionally joined to form a 5-to 7-membered heterocyclic ring; and R¹⁴ is independently chosen fromacyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl;C^(a) and C^(b) are carbon atoms, which are adjacent to each other andare part of ring A; Z is 5- or 6-membered heteroaryl; and (ii) when ringA is thiazole, then Z is not benzoimidazole; R⁵ is chosen from H, acyl,C₁-C₆ alkyl, and C₃-C₆ cycloalkyl; W is chosen from C₁-C₄ alkylene,wherein the alkylene is optionally substituted with 1-4 substituentsindependently chosen from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl, C₃-C₆-cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl,5- or 6-membered heteroaryl, CN, halogen, OR⁴², SR⁴², NR⁴²R⁴³, C(O)R⁴⁴,C(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³, C(O)OR⁴², NR⁴⁵C(O)R⁴⁴, NR⁴⁵C(O)OR⁴²,NR⁴⁵C(O)NR⁴²R⁴³, NR⁴⁵C(S)NR⁴²R⁴³, NR⁴⁵S(O)₂R⁴⁴, S(O)₂NR⁴²R⁴³, S(O)R⁴⁴,and S(O)₂R⁴⁴, wherein R⁴², R⁴³ and R⁴⁵ are members independently chosenfrom H, acyl C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or6-membered heteroaryl, C₃-C₈ cycloalkyl and 3- to 8-memberedheterocycloalkyl, wherein R⁴² and R⁴³, together with the nitrogen atomto which they are bound are optionally joined to form a 5- to 7-memberedheterocyclic ring; and R⁴⁴ is independently chosen from acyl,C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl; Cyis chosen from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl isoptionally substituted with 1-6 substituents independently chosen fromsubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, haloalkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, CN,halogen, OR⁵², SR⁵², NR⁵²R⁵³, C(O)R⁵⁴, C(O)NR⁵²R⁵³, OC(O)NR⁵²R⁵³,C(O)OR⁵², NR⁵⁵C(O)R⁵⁴, NR⁵⁵C(O)OR⁵², NR⁵⁵C(O)NR⁵²R⁵³, NR⁵⁵C(S)NR⁵²R⁵³,NR⁵⁵S(O)₂R⁵⁴, S(O)₂NR⁵²R⁵³, S(O)R⁵⁴ and S(O)₂R⁵⁴, wherein R⁵², R⁵³ andR⁵⁵ are independently chosen from H, acyl C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, wherein R⁵² and R⁵³, together with thenitrogen atom to which they are bound are optionally joined to form a 5-to 7-membered heterocyclic ring; and R⁵⁴ is independently chosen fromacyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl; (ii)adding a kinase substrate and ATP or a derivative thereof to themixture; and (iii) measuring an amount of phosphorylated kinasesubstrate. In one example, the method further comprises measuringphosphorylated kinase substrate, such as phospho-cJun.

The present invention also provides for an in vitro method comprisingcontacting a cell with a compound having a structure according toFormula (I):

or a salt or solvate thereof, wherein ring A is 5-membered heteroarylcomprising a sulfur atom, wherein the heteroaryl is optionallysubstituted with 1 or 2 substituents independently chosen from alkyl,alkenyl, alkynyl, haloalkyl, heteroalkyl, C₃-C₁₀-cycloalkyl, 3- to8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN,halogen, OR¹², SR¹², NR¹²R¹³, C(O)R¹⁴, C(O)NR¹²R¹³, OC(O)NR¹²R¹³,C(O)OR¹², NR¹⁵C(O)R¹⁴, NR¹⁵C(O)OR¹², NR¹⁵C(O)NR¹²R¹³, NR¹⁵C(S)NR¹²R¹³,NR¹⁵S(O)₂R¹⁴, S(O)₂NR¹²R¹³, S(O)R¹⁴ and S(O)₂R¹⁴, wherein R¹², R¹³ andR¹⁵ are independently chosen from H, acyl C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, or R¹² and R¹³, together with thenitrogen atom to which they are bound are optionally joined to form a 5-to 7-membered heterocyclic ring; and R¹⁴ is independently chosen fromacyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl;C^(a) and C^(b) are carbon atoms, which are adjacent to each other andare part of ring A; Z is 5- or 6-membered heteroaryl; R⁵ is chosen fromH, acyl, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl; W is chosen from C₁-C₄alkylene, wherein the alkylene is optionally substituted with 1-4substituents independently chosen from alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl, C₃-C₆-cycloalkyl, 3- to 8-memberedheterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR⁴²,SR⁴², NR⁴²R⁴³, C(O)R⁴⁴, C(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³, C(O)OR⁴²,NR⁴⁵C(O)R⁴⁴, NR⁴⁵C(O)OR⁴², NR⁴⁵C(O)NR⁴²R⁴³, NR⁴⁵C(S)NR⁴²R⁴³,NR⁴⁵S(O)₂R⁴⁴, S(O)₂NR⁴²R⁴³, S(O)R⁴⁴, and S(O)₂R⁴⁴, wherein R⁴², R⁴³ andR⁴⁵ are members independently chosen from H, acyl C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl, wherein R⁴² and R⁴³,together with the nitrogen atom to which they are bound are optionallyjoined to form a 5- to 7-membered heterocyclic ring; and R⁴⁴ isindependently chosen from acyl, C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- to 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl; Cy is chosen from cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl,heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1-6substituents independently chosen from substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, haloalkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, CN, halogen, OR⁵², SR⁵²,NR⁵²R⁵³, C(O)R⁵⁴, C(O)NR⁵²R⁵³, OC(O)NR⁵²R⁵³, C(O)OR⁵², NR⁵⁵C(O)R⁵⁴,NR⁵⁵C(O)OR⁵², NR⁵⁵C(O)NR⁵²R⁵³, NR⁵⁵C(S)NR⁵²R⁵³, NR⁵⁵S(O)₂R⁵⁴,S(O)₂NR⁵²R⁵³, S(O)R⁵⁴ and S(O)₂R⁵⁴, wherein R⁵², R⁵³ and R⁵⁵ areindependently chosen from H, acyl C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, wherein R⁵² and R⁵³, together with thenitrogen atom to which they are bound are optionally joined to form a 5-to 7-membered heterocyclic ring; and R⁵⁴ is independently chosen fromacyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl. Inone example, the method further comprises measuring phosphorylatedkinase substrate, such as phospho-cJun.

DETAILED DESCRIPTION OF THE DISCLOSURE Definitions

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims. Throughout the specification and the appended claims, a givenformula or name shall encompass all isomers thereof, such asstereoisomers, geometrical isomers, optical isomers, tautomers, andmixtures thereof where such isomers exist, as well as pharmaceuticallyacceptable salts and solvates thereof, such as hydrates.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” includes a mixture oftwo or more compounds. It should also be noted that the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

Where multiple substituents are indicated as being attached to astructure, those substituents are independently chosen. For example,“ring A is optionally substituted with 1, 2 or 3 R_(q) groups” indicatesthat ring A is substituted with 1, 2 or 3 R_(q) groups, wherein theR_(q) groups are independently chosen (i.e., can be the same ordifferent).

Compounds were named using Autonom 2000 4.01.305, which is availablefrom Beilstein Information Systems, Inc, Englewood, Colo.; ChemDrawv.10.0, (available from Cambridgesoft at 100 Cambridge Park Drive,Cambridge, Mass. 02140), or ACD Name pro, which is available fromAdvanced Chemistry Development, Inc., at 110 Yonge Street, 14^(th)floor, Toronto, Ontario, Canada M5c 1T4. Alternatively, the names weregenerated based on the IUPAC rules or were derived from names originallygenerated using the aforementioned nomenclature programs. A person ofskill in the art will appreciate that chemical names for tautomericforms of the current compounds will vary slightly, but will neverthelessdescribe the same compound. For example, the namesN-(2-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(naphthalen-1yl)acetamideandN-(2-(5-methyl-4H-1,2,4-triazol-3-yl)thiophen-3-y)-2-(naphthalen-1-yl)acetamidedescribe two tautomeric forms of the same compound.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents, which would result from writing thestructure from right to left. For example, “—CH₂O—” is intended to alsorecite “—OCH₂—”.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical having the number of carbon atoms designated (e.g., C₁-C₁₀ meansone to ten carbon atoms). Typically, an alkyl group will have from 1 to24 carbon atoms, for example having from 1 to 10 carbon atoms, from 1 to8 carbon atoms or from 1 to 6 carbon atoms. A “lower alkyl” group is analkyl group having from 1 to 4 carbon atoms. The term “alkyl” includesdi- and multivalent radicals. For example, the term “alkyl” includes“alkylene” wherever appropriate, e.g., when the formula indicates thatthe alkyl group is divalent or when substituents are joined to form aring. Examples of alkyl radicals include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, iso-butyl,sec-butyl, as well as homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl and n-octyl.

The term “alkylene” by itself or as part of another substituent means adivalent (diradical) alkyl group, wherein alkyl is defined herein.“Alkylene” is exemplified, but not limited, by —CH₂CH₂CH₂CH₂—.Typically, an “alkylene” group will have from 1 to 24 carbon atoms, forexample, having 10 or fewer carbon atoms (e.g., 1 to 8 or 1 to 6 carbonatoms). A “lower alkylene” group is an alkylene group having from 1 to 4carbon atoms.

The term “alkenyl” by itself or as part of another substituent refers toa straight or branched chain hydrocarbon radical having from 2 to 24carbon atoms and at least one double bond. A typical alkenyl group hasfrom 2 to 10 carbon atoms and at least one double bond. In oneembodiment, alkenyl groups have from 2 to 8 carbon atoms or from 2 to 6carbon atoms and from 1 to 3 double bonds. Exemplary alkenyl groupsinclude vinyl, 2-propenyl, 1-but-3-enyl, crotyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), 2-isopentenyl, 1-pent-3-enyl,1-hex-5-enyl and the like.

The term “alkynyl” by itself or as part of another substituent refers toa straight or branched chain, unsaturated or polyunsaturated hydrocarbonradical having from 2 to 24 carbon atoms and at least one triple bond. Atypical “alkynyl” group has from 2 to 10 carbon atoms and at least onetriple bond. In one aspect of the disclosure, alkynyl groups have from 2to 6 carbon atoms and at least one triple bond. Exemplary alkynyl groupsinclude prop-1-ynyl, prop-2-ynyl (i.e., propargyl), ethynyl and3-butynyl.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to alkyl groups that areattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means a stable or branched chain hydrocarbon radical consisting of thestated number of carbon atoms (e.g., C₂-C₁₀, or C₂-C₈) and at least oneheteroatom chosen, e.g., from N, O, S, Si, B and P (in one embodiment,N, O and S), wherein the nitrogen, sulfur and phosphorus atoms areoptionally oxidized, and the nitrogen atom(s) are optionallyquaternized. The heteroatom(s) is/are placed at any interior position ofthe heteroalkyl group. Examples of heteroalkyl groups include, but arenot limited to, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂S(O)₂—CH₃, —CH═CH—O—CH₃,—CH₂—Si(CH₃)₃, —CH₂—CH═N—OCH₃, and CH═CH—N(CH₃)—CH₃. Up to twoheteroatoms can be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃ )₃. Similarly, the term “heteroalkylene” by itself or aspart of another substituent means a divalent radical derived fromheteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—. Typically, a heteroalkyl group will have from 3to 24 atoms (carbon and heteroatoms, excluding hydrogen) (3- to24-membered heteroalkyl). In another example, the heteroalkyl group hasa total of 3 to 10 atoms (3- to 10-membered heteroalkyl) or from 3 to 8atoms (3- to 8-membered heteroalkyl). The term “heteroalkyl” includes“heteroalkylene” wherever appropriate, e.g., when the formula indicatesthat the heteroalkyl group is divalent or when substituents are joinedto form a ring.

The term “cycloalkyl” by itself or in combination with other terms,represents a saturated or unsaturated, non-aromatic carbocyclic radicalhaving from 3 to 24 carbon atoms, for example, having from 3 to 12carbon atoms (e.g., C₃-C₈ cycloalkyl or C₃-C₆ cycloalkyl). Examples ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, 1-cyclohexenyl, 3-cyclohexenyl,cycloheptyl and the like. The term “cycloalkyl” also includes bridged,polycyclic (e.g., bicyclic) structures, such as norbornyl, adamantyl andbicyclo[2.2.1]heptyl. The “cycloalkyl” group can be fused to at leastone (e.g., 1 to 3) other ring chosen from aryl (e.g., phenyl),heteroaryl (e.g., pyridyl) and non-aromatic (e.g., carbocyclic orheterocyclic) rings. When the “cycloalkyl” group includes a fused aryl,heteroaryl or heterocyclic ring, then the “cycloalkyl” group is attachedto the remainder of the molecule via the carbocyclic ring.

The term “heterocycloalkyl”, “heterocyclic”, “heterocycle”, or“heterocyclyl”, by itself or in combination with other terms, representsa carbocyclic, non-aromatic ring (e.g., 3- to 8-membered ring and forexample, 4-, 5-, 6- or 7-membered ring) containing at least one and upto 5 heteroatoms chosen from, e.g., N, O, S, Si, B and P (for example,N, O and S), wherein the nitrogen, sulfur and phosphorus atoms areoptionally oxidized, and the nitrogen atom(s) are optionally quaternized(e.g., from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur),or a fused ring system of 4- to 8-membered rings, containing at leastone and up to 10 heteroatoms (e.g., from 1 to 5 heteroatoms chosen fromN, O and S) in stable combinations known to those of skill in the art.Exemplary heterocycloalkyl groups include a fused phenyl ring. When the“heterocyclic” group includes a fused aryl, heteroaryl or cycloalkylring, then the “heterocyclic” group is attached to the remainder of themolecule via a heterocycle. A heteroatom can occupy the position atwhich the heterocycle is attached to the remainder of the molecule.Exemplary heterocycloalkyl or heterocyclic groups of the presentdisclosure include morpholinyl, thiomorpholinyl, thiomorpholinylS-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, tetrahydropyranyl,piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,homopiperidinyl, homomorpholinyl, homothiomorpholinyl,homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl,dihydropyrrolyl, diydropyrazolyl, dihydropyridyl, dihydropyrimidinyl,dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,tetrahydrothienyl S,S-dioxide, homothiomorpholinyl S-oxide,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

By “aryl” is meant a 5-, 6- or 7-membered, aromatic carbocyclic grouphaving a single ring (e.g., phenyl) or being fused to other aromatic ornon-aromatic rings (e.g., from 1 to 3 other rings). When the “aryl”group includes a non-aromatic ring (such as in1,2,3,4-tetrahydronaphthyl) or heteroaryl group then the “aryl” group islinked to the remainder of the molecule via an aryl ring (e.g., a phenylring). The aryl group is optionally substituted (e.g., with 1 to 5substituents described herein). In one example, the aryl group has from6 to 10 carbon atoms. Non-limiting examples of aryl groups includephenyl, 1-naphthyl, 2-naphthyl, qinoline, indanyl, indenyl,dihydronaphthyl, fluorenyl, tetralinyl, benzo[d][1,3]dioxolyl or6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. In one embodiment, the arylgroup is chosen from phenyl, benzo[d][1,3]dioxolyl and naphthyl. Thearyl group, in yet another embodiment, is phenyl.

The term “arylalkyl” is meant to include those radicals in which an arylgroup or heteroaryl group is attached to an alkyl group to create theradicals -alkyl-aryl and -alkyl-heteroaryl, wherein alkyl, aryl andheteroaryl are defined herein. Exemplary “arylalkyl” groups includebenzyl, phenethyl, pyridylmethyl and the like.

By “aryloxy” is meant the group —O-aryl, where aryl is as definedherein. In one example, the aryl portion of the aryloxy group is phenylor naphthyl. The aryl portion of the aryloxy group, in one embodiment,is phenyl.

The term “heteroaryl” or “heteroaromatic” refers to a polyunsaturated,5-, 6- or 7-membered aromatic moiety containing a least one heteroatom(e.g., 1 to 5 heteroatoms, such as 1-3 heteroatoms) chosen from N, O, S,Si and B (for example, N, O and S), wherein the nitrogen and sulfuratoms are optionally oxidized, and the nitrogen atom(s) are optionallyquaternized. The “heteroaryl” group can be a single ring or be fused toother aryl, heteroaryl, cycloalkyl or heterocycloalkyl rings (e.g., from1 to 3 other rings). When the “heteroaryl” group includes a fused aryl,cycloalkyl or heterocycloalkyl ring, then the “heteroaryl” group isattached to the remainder of the molecule via the heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon- or heteroatom. In one example, the heteroaryl grouphas from 4 to 10 carbon atoms and from 1 to 5 heteroatoms chosen from O,S and N. Non-limiting examples of heteroaryl groups include pyridyl,pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl,pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl,phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl,furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl,tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl,isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridyl,benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl,triazinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl,dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, chromonyl,chromanonyl, pyridyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl,dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl,dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl,pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinylN-oxide, quinolinyl N-oxide, indolyl N-oxide, N-oxide, isoquinolylN-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinylN-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide,thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide,benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide,oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolylN-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide.Exemplary heteroaryl groups include imidazolyl, pyrazolyl, thiadiazolyl,triazolyl, isoxazolyl, isothiazolyl, imidazolyl thiazolyl, oxadiazolyl,and pyridyl. Other exemplary heteroaryl groups include 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, pyrazinyl,2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,pyridin-4-yl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, pyrinyl,2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituentsfor each of the above noted aryl and heteroaryl ring systems are chosenfrom the group of acceptable aryl group substituents described below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above.

Each of the above terms (e.g., “alkyl”, “cycloalkyl”, “heteroalkyl”,heterocycloalkyl”, “aryl” and “heteroaryl”) are meant to include bothsubstituted and unsubstituted forms of the indicated radical. The term“substituted” for each type of radical is explained below. When acompound of the present disclosure includes more than one substituent,then each of the substituents is independently chosen.

The term “substituted” in connection with alkyl, alkenyl, alkynyl,cycloalkyl, heteroalkyl and heterocycloalkyl radicals (including thosegroups referred to as alkylene, heteroalkylene, heteroalkenyl,cycloalkenyl, heterocycloalkenyl, and the like) refers to one or moresubstituents, wherein each substituent is independently chosen from, butnot limited to, 3- to 10-membered heteroalkyl, C₃-C₁₀ cycloalkyl, 3- to10-membered heterocycloalkyl, aryl, heteroaryl, —OR^(a), —SR^(a), ═O,═NR^(a), ═N—OR^(a), —NR^(a)R^(b), -halogen, —SiR^(a)R^(b)R^(c),—OC(O)R^(a), —C(O)R^(c), —C(O)OR^(a), —C(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —NR^(c)C(O)R^(e), —NR^(c)C(O)NR^(a)R^(b),—NR^(c)C(S)NR^(a)R^(b), —NR^(c)C(O)OR^(a), —NR^(c)C(NR^(a)R^(b))═NR^(d),—S(O)R^(e), —S(O)₂R^(e), —S(O)₂NR^(a)R^(b), —NR^(c)S(O)₂R^(a), —CN and—NO₂. R^(a), R^(b), R^(c), R^(d) and R^(e) each independently refer tohydrogen, C₁-C₂₄ alkyl (e.g., C₁-C₁₀ alkyl or C₁-C₆ alkyl), C₃-C₁₀cycloalkyl, C₁-C₂₄ heteroalkyl (e.g., C₁-C₁₀ heteroalkyl or C₁-C₆heteroalkyl), C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl, arylalkyl andheteroarylalkyl, wherein, in one embodiment, R^(e) is not hydrogen. Whentwo of the above R groups (e.g., R^(a) and R^(b)) are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 5-, 6-, or 7-membered ring. For example, —NR^(a)R^(b) is meant toinclude pyrrolidinyl N-alkyl-piperidinyl and morpholinyl.

The term “substituted” in connection with aryl and heteroaryl groups,refers to one or more substituents, wherein each substituent isindependently chosen from, but not limited to, alkyl (e.g., C₁-C₂₄alkyl, C₁-C₁₀ alkyl or C₁-C₆ alkyl), cycloalkyl (e.g., C₃-C₁₀cycloalkyl, or C₃-C₈ cycloalkyl), alkenyl (e.g., C₁-C₁₀ alkenyl or C₁-C₆alkenyl, alkynyl (e.g., C₁-C₁₀ alkynyl or C₁-C₆ alkynyl) heteroalkyl(e.g., 3- to 10-membered heteroalkyl), heterocycloalkyl (e.g., C₃-C₈heterocycloalkyl), aryl, heteroaryl, —R^(a), —OR^(a), —SR^(a), ═O,═NR^(a), ═N—OR^(a), —NR^(a)R^(b), -halogen, —SiR^(a)R^(b)R^(c),—OC(O)R^(a), —C(O)R^(e), —C(O)OR^(a), —C(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —NR^(c)C(O)R^(e), —NR^(c)C(O)NR^(a)R^(b),—NR^(c)C(S)NR^(a)R^(b), —NR^(c)C(O)OR^(a), —NR^(c)C(NR^(a)R^(b))═NR^(d),—S(O)R^(e), —S(O)₂R^(e), —S(O)₂NR^(a)R^(b), —NR^(c)S(O)₂R^(a), —CN and—NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in anumber ranging from zero to the total number of open valences on thearomatic ring system, wherein R^(a), R^(b), R^(c), R^(d) and R^(e) eachindependently refer to hydrogen, C₁-C₂₄ alkyl (e.g., C₁-C₁₀ alkyl orC₁-C₆ alkyl), C₃-C₁₀ cycloalkyl, C₁-C₂₄ heteroalkyl (e.g., C₁-C₁₀heteroalkyl or C₁-C₆ heteroalkyl), C₃-C₁₀ heterocycloalkyl, aryl,heteroaryl, arylalkyl and heteroarylalkyl, wherein, in one embodiment,R^(c) is not hydrogen. When two of the above R groups (e.g., R^(a) andR^(b)) are attached to the same nitrogen atom, they can be combined withthe nitrogen atom to form a 5-, 6-, or 7-membered ring. For example,—NR^(a)R^(b) is meant to include pyrrolidinyl N-alkyl-piperidinyl, andmorpholinyl.

The term “substituted” in connection with aryl and heteroaryl groupsalso refers to one or more fused ring(s), in which two hydrogen atoms onadjacent atoms of the aryl or heteroaryl ring are optionally replacedwith a substituent of the formula -T-C(O)—(CRR′)_(q)-U-, wherein T and Uare independently —NR—, —O—, —CRR′— or a single bond, and q is aninteger from 0 to 3. Alternatively, two of the hydrogen atoms onadjacent atoms of the aryl or heteroaryl ring can optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)-B-, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or asingle bond, and r is an integer from 1 to 4. One of the single bonds ofthe ring so formed can optionally be replaced with a double bond.Alternatively, two of the hydrogen atoms on adjacent atoms of the arylor heteroaryl ring can optionally be replaced with a substituent of theformula (CRR′)_(s)—X—(CR″R′″)_(d)—, where s and d are independentlyintegers from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂)NR′—, wherein the substituents R, R′, R″ and R′″ in each of theformulas above are independently chosen from hydrogen and (C₁-C₆)alkyl.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean at least one of fluorine, chlorine, bromine andiodine.

By “haloalkyl” is meant an alkyl radical, wherein alkyl is as definedabove and wherein at least one hydrogen atom is replaced by a halogenatom. The term “haloalkyl,” is meant to include monohaloalkyl andpolyhaloalkyl. For example, the term “halo(C₁-C₄)alkyl” is mean toinclude, but not limited to, chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and 4-chlorobutyl,3-bromopropyl.

As used herein, the term “acyl” describes the group —C(O)R^(c), whereinR^(c) is chosen from hydrogen, C₁-C₂₄ alkyl (e.g., C₁-C₁₀ alkyl or C₁-C₆alkyl), C₁-C₂₄ alkenyl (e.g., C₁-C₁₀ alkenyl or C₁-C₆ alkenyl), C₁-C₂₄alkynyl (e.g., C₁-C₁₀ alkynyl or C₁-C₆ alkynyl), C₃-C₁₀ cycloalkyl,C₁-C₂₄ heteroalkyl, (e.g., C₁-C₁₀ heteroalkyl or C₁-C₆ heteroalkyl,C₃-C₁₀ heterocycloalkyl, aryl, heteroaryl, arylalkyl andheteroarylalkyl. In one embodiment, R^(c) is not hydrogen.

By “alkanoyl” is meant an acyl radical —C(O)-Alk-, wherein Alk is analkyl radical as defined herein. Examples of alkanoyl include acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, 2-methyl-butyryl,2,2-dimethylpropionyl, hexanoyl, heptanoyl, octanoyl and the like.

As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N),sulfur (S), silicon (Si), boron (B) and phosphorus (P). In oneembodiment, heteroatoms are O, S and N.

By “oxo” is meant the group ═O.

The symbol “R” is a general abbreviation that represents a substituentgroup as described herein. Exemplary substituent groups include alkyl,alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, heteroaryl andheterocycloalkyl groups, each as defined herein.

As used herein, the term “aromatic ring” or “non-aromatic ring” isconsistent with the definition commonly used in the art. For example,aromatic rings include phenyl and pyridyl. Non-aromatic rings includecyclohexanes.

As used herein, the term “fused ring system” means at least two rings,wherein each ring has at least 2 atoms in common with another ring.“Fused ring systems can include aromatic as well as non-aromatic rings.Examples of “fused ring systems” are naphthalenes, indoles, quinolines,chromenes and the like. Likewise, the term “fused ring” refers to a ringthat has at least two atoms in common with the ring to which it isfused.

The phrase “therapeutically effective amount” as used herein means thatamount of a compound, material, or composition of the presentdisclosure, which is effective for producing a desired therapeuticeffect, at a reasonable benefit/risk ratio applicable to any medicaltreatment. For example, a “therapeutically effective amount” is anamount effective to reduce or lessen at least one symptom of the diseaseor condition being treated or to reduce or delay onset of one or moreclinical markers or symptoms associated with the disease or condition,or to modify or reverse the disease process.

The terms “treatment” or “treating” when referring to a disease orcondition, means producing a desired therapeutic effect. Exemplarytherapeutic effects include delaying onset or reducing at least onesymptom associated with the disease, positively affecting (e.g.,reducing or delaying onset) a clinical marker associated with thedisease and slowing or reversing disease progression.

The term “pharmaceutically acceptable” refers to those properties and/orsubstances that are acceptable to a patient (e.g., human patient) from atoxicological and/or safety point of view.

The term “pharmaceutically acceptable salts” means salts of thecompounds of the present disclosure, which may be prepared withrelatively nontoxic acids or bases, depending on the particularsubstituents found on the compounds described herein. When compounds ofthe present disclosure contain relatively acidic functionalities (e.g.,—COOH group), base addition salts can be obtained by contacting thecompound (e.g., neutral form of such compound) with a sufficient amountof the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts includelithium, sodium, potassium, calcium, ammonium, organic amino, magnesiumand aluminum salts and the like. When compounds of the presentdisclosure contain relatively basic functionalities (e.g., amines), acidaddition salts can be obtained, e.g., by contacting the compound (e.g.,neutral form of such compound) with a sufficient amount of the desiredacid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, diphosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic and thelike, as well as the salts derived from relatively nontoxic organicacids like formic, acetic, propionic, isobutyric, malic, maleic,malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, 2-hydroxyethylsulfonic, salicyclic, stearic and thelike. Also included are salts of amino acids such as arginate and thelike, and salts or organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., Journal of PharmaceuticalScience, 1977, 66: 1-19). Certain specific compounds of the presentdisclosure contain both, basic and acidic, functionalities that allowthe compounds to be converted into either base or acid addition salts.

The neutral forms of the compounds can be regenerated, for example, bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compound candiffer from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentdisclosure.

When a substituent includes a negatively charged oxygen atom “O⁻”, e.g.,in “—COO⁻”, then the formula is meant to optionally include a proton oran organic or inorganic cationic counterion (e.g., Na+). In one example,the resulting salt form of the compound is pharmaceutically acceptable.Further, when a compound of the present disclosure includes an acidicgroup, such as a carboxylic acid group, e.g., written as the substituent“—COOH”, “—CO₂H” or “—C(O)₂H”, then the formula is meant to optionallyinclude the corresponding “de-protonated” form of that acidic group,e.g., “—COO^(−”, “—CO) ₂” or “—C(O)₂”, respectively.

In addition to salt forms, the present disclosure provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentdisclosure. Non-limiting examples of “pharmaceutically acceptablederivative” or “prodrug” include pharmaceutically acceptable esters,phosphate esters or sulfonate esters thereof as well as otherderivatives of a compound of this present disclosure which, uponadministration to a recipient, is capable of providing, either directlyor indirectly, a compound of this present disclosure. In one embodiment,derivatives or prodrugs are those that increase the bioavailability ofthe compounds of this present disclosure when such compounds areadministered to a mammal (e.g., by allowing an orally administeredcompound to be more readily absorbed into the blood stream) or whichenhance delivery of the parent compound to a biological compartment(e.g., the brain or lymphatic system) relative to the parent species.

Prodrugs include a variety of esters (i.e., carboxylic acid ester).Ester groups, which are suitable as prodrug groups are generally knownin the art and include benzyloxy, di(C₁-C₆)alkylaminoethyloxy,acetoxymethyl, pivaloyloxymethyl, phthalidoyl, ethoxycarbonyloxyethyl,5-methyl-2-oxo-1,3-dioxol-4-yl methyl, and (C₁-C₆)alkoxy esers,optionally substituted by N-morpholino and amide-forming groups such asdi(C₁-C₆)alkylamino. For example, ester prodrug groups include C₁-C₆alkoxy esters. Those skilled in the art will recognize various syntheticmethodologies that may be employed to form pharmaceutically acceptableprodrugs of the compounds of the present disclosure (e.g., viaesterification of a carboxylic acid group).

In an exemplary embodiment, the prodrug is suitable fortreatment/prevention of those diseases and conditions that require thedrug molecule to cross the blood brain barrier. In one embodiment, theprodrug enters the brain, where it is converted into the active form ofthe drug molecule. In another example, a prodrug is used to enable anactive drug molecule to reach the inside of the eye after topicalapplication of the prodrug to the eye. Additionally, prodrugs can beconverted to the compounds of the present disclosure by chemical orbiochemical methods in an ex vivo environment. For example, prodrugs canbe slowly converted to the compounds of the present disclosure whenplaced in a transdermal patch reservoir with a suitable enzyme orchemical reagent.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and areencompassed within the scope of the present disclosure. Certaincompounds of the present disclosure can exist in multiple crystalline oramorphous forms (“polymorphs”). In general, all physical forms are ofuse in the methods contemplated by the present disclosure and areintended to be within the scope of the present disclosure. “Compound ora pharmaceutically acceptable salt, hydrate, polymorph or solvate or acompound” intends the inclusive meaning of “and/or”, in that materialsmeeting more than one of the stated criteria are included, e.g., amaterial that is both a salt and a solvate is encompassed.

The compounds of the present disclosure can contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds can beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present disclosure, whether radioactive or not, areintended to be encompassed with the scope of the present disclosure.Compounds described herein, in which one or more of the hydrogen atomsare replaced with another stable isotope of hydrogen (i.e., deuterium)or a radioactive isotope (i.e., tritium), are part of this disclosure.

Compositions Including Stereoisomers

Compounds of the present disclosure can exist in particular geometric orstereoisomeric forms. The present disclosure contemplates all suchcompounds, including cis- and trans-isomers, (−)- and (+)-enantiomers,diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof,and other mixtures thereof, such as enantiomerically ordiastereomerically enriched mixtures, as falling within the scope of thepresent disclosure. Additional asymmetric carbon atoms can be present ina substituent such as an alkyl group. All such isomers, as well asmixtures thereof, are intended to be included in this disclosure. Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms and mixtures of tautomers are included.

Optically active (R)- and (S)-isomers and d and l isomers can beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. Resolution of the racemates can beaccomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent; chromatography,using, for example a chiral HPLC column; or derivatizing the racemicmixture with a resolving reagent to generate diastereomers, separatingthe diastereomers via chromatography, and removing the resolving agentto generate the original compound in enantiomerically enriched form. Anyof the above procedures can be repeated to increase the enantiomericpurity of a compound. If, for instance, a particular enantiomer of acompound of the present disclosure is desired, it can be prepared byasymmetric synthesis, or by derivatization with a chiral auxiliary,where the resulting diastereomeric mixture is separated and theauxiliary group cleaved to provide the pure desired enantiomers.Alternatively, where the molecule contains a basic functional group,such as an amino group, or an acidic functional group, such as acarboxyl group, diastereomeric salts can be formed with an appropriateoptically active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means known in the art, and subsequent recovery of thepure enantiomers. In addition, separation of enantiomers anddiastereomers is frequently accomplished using chromatography employingchiral, stationary phases, optionally in combination with chemicalderivatization (e.g., formation of carbamates from amines).

As used herein, the term “chiral”, “enantiomerically enriched” or“diastereomerically enriched” refers to a compound having anenantiomeric excess (ee) or a diastereomeric excess (de) of greater thanabout 50%, for example, greater than about 70%, such as greater thanabout 90%. In one embodiment, the compositions have higher than about90% enantiomeric or diastereomeric excess, e.g., those compositions withgreater than about 95%, greater than about 97% and greater than about99% ce or de.

The terms “enantiomeric excess” and “diastereomeric excess” are used intheir conventional sense. Compounds with a single stereocenter arereferred to as being present in “enantiomeric excess”, those with atleast two stereocenters are referred to as being present in“diastereomeric excess”. The value of ee will be a number from 0 to 100,zero being racemic and 100 being enantiomerically pure. For example, a90% ee reflects the presence of 95% of one enantiomer and 5% of theother(s) in the material in question.

Hence, in one embodiment, the disclosure provides a compositionincluding a first stereoisomer and at least one additional stereoisomerof a compound of the present disclosure. The first stereoisomer can bepresent in a diastereomeric or enantiomeric excess of at least about80%, such as at least about 90%, and for example, at least about 95%. Inanother embodiment, the first stereoisomer is present in adiastereomeric or enantiomeric excess of at least about 96%, at leastabout 97%, at least about 98%, at least about 99% or at least about99.5%. In yet another embodiment, the compounds of the presentdisclosure is enantiomerically or diastereomerically pure(diastereomeric or enantiomeric excess is about 100%). Enantiomeric ordiastereomeric excess can be determined relative to exactly one otherstereoisomer, or can be determined relative to the sum of at least twoother stereoisomers. In an exemplary embodiment, enantiomeric ordiastereomeric excess is determined relative to all other detectablestereoisomers, which are present in the mixture. Stereoisomers aredetectable if a concentration of such stereoisomer in the analyzedmixture can be determined using common analytical methods, such aschiral HPLC.

The term “JNK-mediated condition”, “c-Jun N-terminal kinase mediateddisorder” or any other variation thereof, as sued herein means anydisease or other condition in which JNK is known to play a role, or adisease state that is associated with elevated activity or expression ofJNK. For example, a “JNK-mediated condition” may be relieved byinhibiting JNK activity. Such conditions include, without limitation,inflammatory diseases, autoimmune disease, destructive bone disorders,proliferative disorders, cancer, infectious diseases, neurodegenerativediseases, allergies, reperfusion/ischemia in stroke, heart attacks,angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiachypertrophy, thrombin-induced platelet aggregation, and conditionsassociated with prostaglandin endoperoxidase synthase-2.

The term “neurological disorder” refers to any undesirable condition ofthe central or peripheral nervous system of a mammal. The term“neurological disorder” includes neurodegenerative diseases (e.g.,Alzheimer's disease, Parkinson's disease and amyotrophic lateralsclerosis), neuropsychiatric diseases (e.g. schizophrenia and anxieties,such as general anxiety disorder). Exemplary neurological disordersinclude MLS (cerebellar ataxia), Huntington's disease, Down syndrome,multi-infarct dementia, status epilecticus, contusive injuries (e.g.spinal cord injury and head injury), viral infection inducedneurodegeneration, (e.g. AIDS, encephalopathies), epilepsy, benignforgetfulness, closed head injury, sleep disorders, depression (e.g.,bipolar disorder), dementias, movement disorders, psychoses, alcoholism,post-traumatic stress disorder and the like. “Neurological disorder”also includes any undesirable condition associated with the disorder.For instance, a method of treating a neurodegenerative disorder includesmethods of treating loss of memory and/or loss of cognition associatedwith a neurodegenerative disorder. Such method would also includetreating or preventing loss of neuronal function characteristic ofneurodegenerative disorder.

The term “neurodegenerative diseases” incudes any disease or conditioncharacterized by problems with movements, such as ataxia, and conditionsaffecting cognitive abilities (e.g., memory) as well as conditionsgenerally related to all types of dementia. “Neurodegenerative diseases”may be associated with impairment or loss of cognitive abilities,potential loss of cognitive abilities and/or impairment or loss of braincells. Exemplary “neurodegenerative diseases” include Alzheimer'sdisease (AD), diffuse Lewy body type of Alzheimer's disease, Parkinson'sdisease, Down syndrome, dementia, mild cognitive impairment (MCI),amyotrophic lateral sclerosis (ALS), traumatic brain injuries, ischemia,stroke, cerebral ischemic brain damage, ischemic or hemorrhaging stroke,multi-infarct dementia, hereditary cerebral hemorrhage with amyloidosisof the dutch-type, cerebral amyloid angiopathy (including single andrecurrent lobar hemorrhages), neurodegeneration induced by viralinfection (e.g., AIDS, encephalopathies) and other degenerativedementias, including dementias of mixed vascular and degenerativeorigin, dementia associated wit Parkinson's disease, dementia associatedwith progressive supranuclear palsy and dementia associated withcortical basal degeneration, epilepsy, seizures, and Huntington'sdisease.

“Pain” is an unpleasant sensory and emotional experience. Painclassifications have been based on duration, etiology orpathophysiology, mechanism, intensity, and symptoms. The term “pain” asused herein refers to all categories of pain, including pain that isdescribed in terms of stimulus or nerve response, e.g., somatic pain(normal nerve response to a noxious stimulus) and neuropathic pain(abnormal response of a injured or altered sensory pathway, oftenwithout clear noxious input); pain that is categorized temporally, e.g.,chronic pain and acute pain; pain that is categorized in terms of itsseverity, e.g., mild, moderate, or severe; and pain that is a symptom ora result of a disease state or syndrome, e.g., inflammatory pain, cancerpain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiacischaemia, and diabetic peripheral neuropathic pain (see, e.g.,Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al.,eds., 12th ed. 1991), Williams et al., J. of Med. Chem. 42: 1481-1485(1999), herein each incorporated by reference in their entirety). “Pain”is also meant to include mixed etiology pain, dual mechanism pain,allodynia, causalgia, central pin, hyperesthesia, hyperpathia,dysesthesia, and hyperalgesia.

Compositions

In various aspects, the present disclosure provides a compound having astructure according to Formula (I):

or a salt thereof.

In Formula (I), ring A is chosen from substituted or unsubstituted aryl(e.g., phenyl) and substituted or unsubstituted heteroaryl. In oneexample, ring A is a 5-membered heteroaromatic ring. In one example, the5-membered heteroaromatic ring comprising from 1 to 3 heteroatoms chosenfrom O, S and N (e.g., thiophene, thiazole, or oxazole). In anotherexample, ring A is a 5-membered heteroaromatic ring containing at leastone sulfur atom (e.g., thiophene, thiazole). In another example, ring Ais a 6-membered heteroaromatic ring. In one example, the 6-memberedheteroaromatic ring comprises from 1 to 4 heteroatoms chosen from O, Sand N (e.g., pyridyl or pyrimidyl). The above 6-membered heteroaromaticring is optionally substituted with from 1 to 3 substituents, and theabove 5-membered heteroaromatic ring is optionally substituted with 1 or2 substituents, wherein each substituent is independently chosen fromsubstituted or unsubstituted alkyl (e.g., C₁-C₆-alkyl), substituted orunsubstituted alkenyl (e.g., C₁-C₆-alkenyl), substituted orunsubstituted alkyl (e.g. C₁-C₆-alkynyl), haloalkyl (e.g.,C₁-C₆-haloalkyl), substituted or unsubstituted heteroalkyl (e.g., 2- to6-membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g.,C₃-C₆-cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3- to 8-membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., 5- or6-membered heteroaryl), CN, halogen, OR¹², SR¹², NR¹²R¹³, C(O)R¹⁴,C(O)NR¹²R¹³, OC(O)NR¹²R¹³, C(O)OR¹², NR¹⁵C(O)R¹⁴, NR¹⁵C(O)OR¹²,NR¹⁵C(O)NR¹²R¹³, NR¹⁵C(S)NR¹²R¹³, NR¹⁵S(O)₂R¹⁴, S(O)₂NR¹²R¹³, S(O)R¹⁴and S(O)₂R¹⁴, wherein R¹², R¹³ and R¹⁵ are independently chosen from H,acyl C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl,wherein R¹² and R¹³, together with the nitrogen atom to which they arebound are optionally joined to form a 5- to 7-membered heterocyclicring. R¹⁴ is independently chosen from acyl, C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- to 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl.

In Formula (I), C^(a) and C^(b) are carbon atoms, which are adjacent toeach other and are both part of ring A.

In Formula (I), Z is a 5- or 6-membered heteroaromatic ring (e.g.,triazole, oxazole, oxadiazole, imidazole, tetrazole, pyrazole, pyridine,pyrazine and the like). Exemplary Z groups are described herein below.

In one example, when ring A is thiophene, then Z is not a thiazole-2-ylor benzo[d]thiazol-2-yl. In another example, when ring A is thiophene,then Z is not 1H-benzo[d]imidazole-2-yl. In yet another example, whenring A is thiophene, then Z is not methyl or ethyl-substituted thiazole.In another example, when ring A is thiophene, then Z is not substituted(e.g., alkyl-substituted) or unsubstituted thiazoles and substituted orunsubstituted benzothiazoles. In another example, when ring A isthiophene, then Z is not substituted or unsubstituted benzimidazoles. Ina further example, when ring A is thiazole, then Z is not substituted orunsubstituted benzimidazoles. In yet another example, when ring A isthiazole, then Z is not 1H-benzo[d]imidazole-2-yl.

In one example, when A is thiophene, then Z is not:

In another example, when A is thiopene, then Z is not:

In a further example, when A is thiophene, then Z is not:

In another example, when A is thiophene or thiazole, then Z is not:

In one example, when ring A is thiophene, then Z is other thanoxadiazole. In another example, when ring A is thiophene, then Z isother than substituted (e.g., phenyl-substituted) oxadiazole. In yetanother example, when ring A is thiophene, then Z is other thanoxadiazole substituted with phenyl or substituted phenyl. In yet anotherexample, when ring A is thiophene, then Z is other than oxadiazole,wherein the oxadiazole is substituted with a phenyl, 4-methyl-phenyl, ora 4-ethyl-phenyl group. In another example, when ring A is methyl- orethyl-substituted thiophene, then Z is other than oxadiazole.

In another example, when ring A is thiophene, then Z is other thanpyrimidinone. In another example, when ring A is thiophene, then Z isother than substituted pyrimidinone (e.g., pyrimidinone substituted withat least one of hydroxy, carboxy or hydroxy-methylene).

In Formula (I), R⁵ is chosen from H, substituted or unsubstituted alkyl(e.g., C₁-C₆ alkyl), substituted or unsubstituted C₃-C₆ cycloalkyl andacyl (e.g., acetyl).

In Formula (I), W is chosen from substituted or unsubstituted alkylene(e.g., substituted or unsubstituted C₁-C₁₀ alkylene). In one example, Wis C₁-C₁₀ alkylene optionally substituted with from 1 to 6 substituentschosen from R¹⁰ and R¹¹ defined as hereinbelow for Formulae (X) and(XI). In another example, W is straight chain alkylene represented bythe formula —(CR¹⁰R¹¹)_(n)—, wherein n is chosen from 1 to 10 and R¹⁰and R¹¹ are defined as hereinbelow for Formulae (X) and (XI). In yetanother example, W is a straight carbon chain represented by—(CH₂)_(n)—, wherein n is from 1 to 10 (e.g., n is chosen from from 1 to3 or n is 1 or 2). In another example W is C₁-C₄ alkylene optionallysubstituted with from 1 to 4 substituents chosen from R¹⁰ and R¹¹ asdefined herein. In a further example, W is substituted or unsubstitutedmethylene, e.g., —CR¹⁰R¹¹—, wherein R¹⁰ and R¹¹ are defined ashereinbelow for Formulae (X) and (XI). In a further example, W ismethylene, optionally substituted with one or two substituents chosenfrom C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, CN and halogen (e.g.,F, Cl or Br). In a one example, W is unsubstituted methylene (—CH₂—).

Cy in Formula (I) represents a ring or fused ring system. In oneexample, Cy is chosen from substituted or unsubstituted cycloalkyl(e.g., substituted or unsubstituted C₃-C₈ cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., substituted or unsubstituted 3- to8-membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.,phenyl), substituted or unsubstituted heteroaryl (e.g., pyridyl) and afused ring system. Exemplary Cy are described hereinbelow.

In one example, ring Z in Formula (I) is a 5-membered heteroaromaticring and the compound of the present disclosure has a structureaccording to Formula (II):

or a salt or solvate thereof, wherein A, C^(a), C^(b), R⁵, W and Cy aredefined as for Formula (I), above.

In Formula (II), Y¹ is chosen from N, O and S. Y², Y³ and Y⁴ areindependently chosen from S, O, N, NR³ and CR⁴. In one example, at leastone of Y¹ and Y² is N. Each R³ and each R⁴ is independently chosen fromH, substituted or unsubstituted alkyl (e.g., C₁-C₆-alkyl), substitutedor unsubstituted alkenyl (e.g., C₁-C₆-alkenyl), substituted orunsubstituted alkynyl (e.g., C₁-C₆-alkynyl), haloalkyl (e.g.,C₁-C₆-haloalkyl), substituted or unsubstituted heteroalkyl (e.g., 2- to6-membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g.,C₁-C₆-cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3- to 8-membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., 5- or6-membered heteroaryl), CN, halogen, OR¹⁷, SR¹⁷, NR¹⁷R¹⁸, C(O)R¹⁹,C(O)NR¹⁷R¹⁸, OC(O)NR¹⁷R¹⁸, C(O)OR¹⁷, NR²⁰C(O)R¹⁹, NR²⁰C(O)OR¹⁷,NR²⁰C(O)NR¹⁷R¹⁸, NR²⁰C(S)NR¹⁷R¹⁸, NR²⁰S(O)₂R¹⁹, S(O)₂NR¹⁷R¹⁸, S(O)R¹⁹and S(O)₂R¹⁹, wherein R¹⁷, R¹⁸ and R²⁰ are independently chosen from H,acyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl,wherein R¹⁷ and R¹⁸, together with the nitrogen atom to which they arebound are optionally joined to form a 5- to 7-membered heterocyclicring. R¹⁹ is independently chosen from acyl, C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, (e.g., phenyl), 5- to 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl. Inone example, each R³ is independently chosen from H, alkyl (e.g.,C₁-C₆-alkyl), alkenyl (e.g., C₁-C₆-alkenyl), alkynyl (e.g.,C₁-C₆-alkynyl) haloalkyl (e.g., C₃-C₆-haloalkyl), heterocycloalkyl(e.g., 3- to 8-membered heterocycloalkyl), cycloalkyl (e.g.,C₃-C₆-cycloalkyl), aryl (e.g., phenyl) and heteroaryl. In anotherexample, each R⁴ is independently chosen from H, alkyl (e.g.,C₁-C₆-alkyl), alkenyl (e.g., C₁-C₆-alkenyl), alkynyl (e.g.,C₁-C₆-alkynyl), haloalkyl (e.g., C₁-C₆-haloalkyl), heterocycloalkyl(e.g., 3- to 8-membered heterocycloalkyl), cycloalkyl (e.g.,C₃-C₆-cycloalkyl), aryl (e.g., phenyl), heteroaryl, CN, halogen, OR¹⁷,SR¹⁷ and NR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are defined as above.

Alternatively, any of the R³ substituents and/or R⁴ substituents,together with the atoms to which they are attached, form a 5- to7-membered ring. For example, if two of Y², Y³, and Y⁴ are NR³, then thetwo R³ groups may form a 5- to 7-membered ring. In another embodiment,if two of Y², Y³, and Y⁴ are CR⁴, then the two R⁴ groups may form a 5-to 7-membered ring. In yet another embodiment, if one of Y², Y³, and Y⁴is NR³ and a second of Y², Y³, and Y⁴ is CR⁴, then the R³ and R⁴ groupsmay form a 5- to 7-membered ring.

In another example, in Formula (II), Y¹ is N. In a further example, Y¹is N and Y², Y³ and Y⁴ form a triazole, thiazole, oxazole, oxadiazole,imidazole, pyrazole or tetrazole ring. In yet another example, Y¹ is Nand Y², Y³ and Y⁴ form a triazole ring.

In one example, in Formula (II), when Y³ and Y⁴ are both CR⁴ and Y¹ isN, then Y² is other than S. In another example, when Y³ and Y⁴ are bothCR⁴ and Y² is N, then Y¹ is other than S. In a further example, when Ais thiophene, then the moiety:

is not thiazole. In a further example, when A is thiophene, then theabove moiety is not benzothiazole. In a further example, when A isthiophene, then the above moiety is not benzimidazole. In a furtherexample, when A is thiazole, then the moiety is other thanbenzimidazole. In a further example, when A is thiophene or thiazole,then the above moiety is not thiazole-2-yl, benzo[d]thiazol-2-yl or1H-benzo[d]imidazole-2-yl.

In another example, in Formula (II), when Y² is NR³, then R³ is H. Inanother example, in Formula (II), when Y² is CR⁴, then R⁴ is H.

In another example, in Formula (II), W is substituted or unsubstitutedmethylene. In a further example, W is —CH₂—. In another example, each R³is H. In yet another example, each R⁴ is chosen from H and methyl. In afurther example, in Formula (II), R⁵ is H. In another example, inFormula (II), W is methylene and R⁵ is H.

Ring A

In one example, in Formula (I) and Formula (II), ring A is a 5-memberedheteroaromatic ring. In another example, in Formula (I) and Formula(II), ring A is a 6-membered aromatic or heteroaromatic ring. Exemplaryrings for A include phenyl, pyridine, thiophene, thiazole and oxazole.In a one example, in Formula (I) or (II), ring A is chosen fromthiophene and thiazole. In another example, in Formula (I) or (II), ringA is chosen from thiophene and thiazole, wherein the thiophene isoptionally substituted with 1 or 2 substituents and the thiazole isoptionally substituted with 1 substituent, wherein each substituent isindependently chosen from C₁-C₄ alkyl (e.g., methyl, ethyl, iso-propyl,tert-butyl), C₃-C₆ cycloalkyl (e.g., cyclopropyl), C₁-C₄ haloalkyl(e.g., CF₃, CHF₂, CH₂F, CH₂CF₃), halogen (e.g., F, Cl, Br) and CN. Inanother example, ring A is thiophene or thiazole, Y¹ is N and Y², Y³ andY⁴ form a triazole ring.

In yet another example, ring A is a 5-membered heteroaromatic ring andthe compounds of Formula (II) have a structure according to Formula(IIIa) or Formula (IIIb):

or a salt or solvate thereof, wherein Z, R⁵, W, Cy, Y¹, Y², Y³ and Y⁴are defined as for Formula (I) and Formula (II), above.

In Formula (IIIa) and (IIIb), X¹ X² and X³ are independently chosen fromS, O, N, NR¹ and CR², with the proviso that at least one of X¹, X² andX³ is other than CR². R¹ is chosen from H, substituted or unsubstitutedalkyl (e.g., C₁-C₆-alkyl), substituted or unsubstituted alkenyl (e.g.,C₁-C₆-alkenyl), substituted or unsubstituted alkynyl (e.g.,C₁-C₆-alkynyl), haloalkyl (e.g., C₁-C₆-haloalkyl), substituted orunsubstituted cycloalkyl (e.g., C₃-C₆-cycloalkyl), substituted orunsubstituted heterocycloalkyl (e.g., 3- to 8-memberedheterocycloalkyl), substituted or unsubstituted aryl (e.g., phenyl),substituted or unsubstituted heteroaryl (e.g., pyridyl). In one example,R¹ is chosen from H, substituted or unsubstituted C₁-C₆ alkyl (e.g.,methyl or ethyl) and C₁-C₃ haloalkyl.

In Formula (IIIa) and (IIIb), each R₂ is independently chosen from arylgroup substituents as defined herein. In one example, each R² isindependently chosen from H, substituted or unsubstituted alkyl (e.g.,C₁-C₆-alkyl), substituted or unsubstituted alkenyl (e.g.,C₁-C₆-alkenyl), substituted or unsubstituted alkynyl (e.g.,C₁-C₆-alkynyl), haloalkyl (e.g., C₁-C₆-haloalkyl), substituted orunsubstituted heteroalkyl (e.g., 2- to 6-membered heteroalkyl),substituted or unsubstituted cycloalkyl (e.g., C₃-C₆-cycloalkyl),substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-memberedheterocycloalkyl), substituted or unsubstituted aryl (e.g., phenyl),substituted or unsubstituted heteroaryl (e.g., 5- or 6-memberedheteroaryl), CN, halogen, OR²², SR²², NR²²R²³, C(O)R²⁴, C(O)NR²²R²³,OC(O)NR²²R²³, C(O)OR²², NR²⁵C(O)R²⁴, NR²⁵C(O)OR²², NR²⁵C(O)NR²²R²³,NR²⁵C(S)NR²²R²³, NR²⁵S(O)₂R²⁴, S(O)₂NR²²R²³, S(O)R²⁴ and S(O)₂R²⁴,wherein R²², R²³ and R²⁵ are independently chosen from H, acyl,C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl,wherein R¹² and R¹³, together with the nitrogen atom to which they arebound are optionally joined to form a 5- to 7-membered heterocyclicring. R²⁴ is independently chosen from acyl, C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- to 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl. In one example, eachR² is independently chosen from H, C₁-C₄ alkyl, (e.g., methyl, ethyl,iso-propyl, tert-butyl), C₃-C₆ cycloalkyl (e.g., cyclopropyl), C₁-C₄haloalkyl (e.g., CF₃, CHF₂, CH₂F, CH₂CF₃), halogen (e.g., F, Cl, Br) andCN.

In a further example, the compounds of the present disclosure have astructure according to Formula (IV), Formula (V), Formula (VI) orFormula (VII):

or a salt or solvate thereof, wherein Cy, W, R⁵, Y¹, Y², Y³ and Y⁴ aredefined as hereinabove in Formulae (I), (II), and (III), respectively.

In Formulae (IV) to (VII), R² and R^(2a) are each defined as R² inFormula (IIIa) and (IIIb). In one example, R² and R^(2a) areindependently chosen from H, C₁-C₄ alkyl (e.g., methyl, ethyl,iso-propyl, tert-butyl), C₃-C₆ cycloalkyl (e.g., cyclopropyl), C₁-C₄haloalkyl (e.g., CF₃, CHF₂, CH₂F, CH₂CF₃), halogen (e.g., F, Cl, Br) andCN. In another example, R² and R^(2a) are both H. In yet anotherexample, at least one of R² and R^(2a) is halogen (e.g., F, Cl, Br). Ina further example, at least one of R² and R^(2a) is CN. In anotherexample, at least one of R² and R^(2a) is methyl.

Ring Z

In one embodiment, ring Z is chosen from 5-membered and 6-memberedheteroaromatic rings. Exemplary 6-membered heteroaromatic rings for Zinclude pyridines and pyrazines. In vitro biological activity of thecompounds of the present disclosure is generally higher when ring Z isconnected to ring A via a carbon atom of ring Z (as shown above inFormulae II-VII) as opposed to being connected via a nitrogen atom ofring Z. Hence, in one example, ring Z is connected to the remainder ofthe molecule via a carbon atom.

In vitro biological activity of a compound of the present disclosure isgenerally higher when Z does not include a substituent (e.g., a methylgroup) at the atom, which is immediately adjacent to the ring connectionconnecting rings Z and A. Hence, in another example, when Y² is NR³,then R³ is H. In another example, when Y² is CR⁴, then R⁴ is H.

Exemplary 5-membered heteroaromatic rings for Z in Formula (I) or (IIIb)or the moiety:

in Formula (II), (IIIa) and (IV) to (VII) include triazoles (e.g.,1,2,3-triazoles or 1,2,4-triazoles), oxazoles, isoxazoles, thiazoles,isothiazoles, tetrazoles, oxadiazoles (e.g., 1,2,4-oxadiazoles or1,3,4-oxadiazoles), thiadiazoles (e.g., 1,2,4-thiadiazoles or1,3,4-thiadiazoles), pyrazoles, imidazoles and tetrazoles. In anotherexample, ring Z has a structure, which is chosen from:

wherein Y⁵ is chosen from O, S and NR³, wherein R³ is defined as formFormula (II), above. In one example, each R³ is independently chosenfrom H, alkyl (e.g., C₁-C₆-alkyl), alkenyl (e.g., C₁-C₆-alkenyl),alkynyl (e.g., C₁-C₆-alkynyl), haloalkyl (e.g., C₁-C₆-haloalkyl),heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl), cycloalkyl(e.g., C₃-C₆-cycloalkyl), aryl (e.g., phenyl) and heteroaryl. In anotherexample, R³ in the above structures is chosen from H, C₁-C₃ alkyl (e.g.,methyl) and C₁-C₃ haloalkyl.

In the above structures R⁴ and R^(4a) are independently chosen and areeach defined as R⁴ in Formula (II), above. In one example, R⁴ and R^(4a)are independently chosen from H, alkyl (e.g., C₁-C₆-alkyl), alkenyl(e.g., C₁-C₆-alkenyl), alkynyl (e.g., C₁-C₆-alkynyl), haloalkyl (e.g.,C₁-C₆-haloalkyl), heterocycloalkyl (e.g., 3- to 8-memberedheterocycloalkyl), cycloalkyl (e.g., C₃-C₆-cycloalkyl), aryl (e.g.,phenyl), heteroaryl, CN, halogen, OR¹⁷, SR¹⁷ and NR¹⁷R¹⁸, wherein R¹⁷and R¹⁸ are defined as above. In another example, R⁴ and R^(4a) in theabove structures are independently chosen from H, substituted orunsubstituted C₁-C₃ alkyl (e.g., methyl), C₃-C₆ cycloalkyl (e.g.,cyclopropyl) and NR¹⁷R¹⁸. In another R^(4a) in the above structures isH. In yet another example in the above structures, R⁴ is H. In yetanother example R³ in the above structures is H. In a further example inthe above structures, R³, R⁴ and R^(4a) are each H.

Alternatively, any of the R³ substituents and/or R⁴ substituents,together with the atoms to which they are attached, form a 5- to7-membered ring. For example, if two of Y², Y³, and Y⁴ and NR³, then thetwo R³ groups may form a 5- to 7membered ring. In another embodiment, iftwo of Y², Y³, and Y⁴ are CR⁴, then the two R⁴ groups may form a 5- to7-membered ring. In yet another embodiment, if one of Y², Y³, and Y⁴ isNR³ and a second of Y², Y³, and Y⁴ is CR⁴, then the R³ and R⁴ groups mayform a 5- to 7-membered ring.

In one example, ring Z in Formula (I) or (IIIb) or the moiety:

is any of the above formulae and embodiments, is chosen from:

or a tautomer or mixture of tautomers thereof, wherein R⁴, R^(4a) and R³are defined as hereinabove. In one example, R⁴, R^(4a) and R³ areindependently chosen from H, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, OR¹⁷ andNR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are independently chosen from H,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, and wherein R¹⁷ and R¹⁸,together with the nitrogen atom to which they are attached, areoptionally joined to form a 5- to 7-membered ring. In the abovestructures, at least two of R³, R4 and R^(4a), R¹⁷ and R¹⁸, togetherwith the atoms to which they are attached, are optionally joined to forma 5- to 7-membered ring. For example, one of R³, R⁴ and R^(4a) and oneof R¹⁷ and R¹⁸, together with the atoms to which they are attached, areoptionally joined to form a 5- to 7-membered ring. In another example,R³ and R⁴ or R⁴ and R^(4a), together with the atoms to which they areattached, are optionally joined to form a 5- to 7-membered ring. In oneembodiment, in any of the above structures, R³ is H.

In one embodiment, in the above structures, R^(4a) is H. In anotherembodiment, in the above structures, R⁴ is H, methyl, cyclopropyl oramino. In yet another embodiment, in the above structures, R^(4a) (whenpresent) is H and R⁴ is H. In yet another embodiment, in the abovestructures, R^(4a) (when present) is H and R⁴ is methyl. In a furtherembodiment, in the above structures, R^(4a) (when present) is H and R⁴is cyclopropyl.

In one example, Z in Formula (I) or (IIIb) or the moiety:

in any of the above formulae and embodiments, is chosen from:

or a tautomer or mixture of tautomers thereof.

In one embodiment, Z in Formula (I) or (IIIb) or any of the formulaeabove is a triazole. In one example according to this embodiment, Z hasthe formula:

wherein R³, R¹⁷ and R¹⁸ are defined as herein above. In one example, inthe above structure, R³ and one of R¹⁷ and R¹⁸, together with the atomsto which they are attached, are optionally joined to form a 5- to7-membered ring. In another example, in the above structure, R³ is H.

In another example, Z in formula (I) is a triazole and the compounds ofthe present disclosure have a structure according to Formula (VIIIa),Formula (VIIIb) or Formula (VIIIc):

or a tautomer, mixture of tautomers, salt or solvate thereof.

In Formulae (VIIIa), (VIIIb) and (VIIIc), ring A, C^(a), C^(b), R³, R⁴,R⁵, W and Cy are defined as hereinabove. In one example, R⁴ is H. Inanother example, R⁴ is methyl. In Formula (VIIIb), R³ and R⁴, togetherwith the atoms to which they are attached, are optionally joined to forma 5- to 7-membered ring.

In one example, in Formula (VIIIa), ring A is chosen from thiophenes andthiazoles, In a further example, the compounds of the present disclosurehave a structure according to one of Formula (IVa), Formula (Va),Formula (VIa) and Formula (VIIa):

or a tautomer, mixture of tautomers, salt or solvate thereof, whereinCy, W, R⁴ and R⁵ are defined as for Formula (I), above, R² and R^(2a)are defined as in Formulae (IV) to (VII) hereinabove. In one example, R⁴is H or methyl.

Exemplary 6-membered heteroaromatic rings for Z, e.g., in Formula (I)and Formula (IIIb), include pyridines, pyrazines, pyrimidines,pyridazines and triazines (e.g., 1,2,3-triazines; 1,2,4-triazines or1,3,5-triazines). In one example, Z in Formula (I) or (IIIb) has astructure, which is chosen from:

wherein n is an integer chosen from 0 to 4, m is an integer chosen from0 to 3 and o is an integer chosen from 0 to 2. Each R¹⁶ is independentlychosen from H, substituted or unsubstituted alkyl (e.g., C₁-C₆-alkyl),substituted or unsubstituted alkenyl (e.g., C₁-C₆-alkenyl), substitutedor unsubstituted alkynyl (e.g., C₁-C₆-alkynyl), haloalkyl (e.g.,C₁-C₆-haloalkyl), substituted or unsubstituted heteroalkyl (e.g., 2- to6-membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g.,C₃-C₆-cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3- to 8-membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., 5- or6-membered heteroaryl), CN, halogen, OR³², SR³², NR³²R³³, C(O)R³⁴,C(O)NR³²R³³, OC(O)NR³²R³³, C(O)OR³², NR³⁵C(O)R³⁴, NR³⁵C(O)OR³²,NR³⁵C(O)NR³²R³³, NR³⁵C(S)NR³²R³³, NR³⁵S(O)₂R³⁴, S(O)₂NR³²R³³, S(O)R³⁴and S(O)₂R³⁴, wherein R³², R³³ and R³⁵ are independently chosen from H,acyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl,wherein R³² and R³³, together with the nitrogen atom to which they arebound are optionally joined to form a 5- to 7-membered heterocyclicring. R³⁴ is independently chosen from acyl, C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- to 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl. Adjacent R¹⁶, togetherwith the carbon atoms to which they are attached, are optionally joinedto form a 5- to 7-membered ring.

In another example, Z is a fused ring system, which includes at leastone of the above 5- or 6-membered rings. In one example, Z is chosenfrom benzo- or pyrido-imidazole, benzo- or pyrido-oxazole, benzo- orpyrido-thiazole, benzo- or pyrido-isoxazole and benzo- orpyrido-isothiazole.

In one example, when ring A is thiophene, then Z is other thanoxadizole. In another example, when ring A is thiophene, then Z is otherthan substituted (e.g., phenyl-substituted) oxadiazole. In yet anotherexample, when ring A is thiophene, then Z is other than oxadiazolesubstituted with phenyl or substituted phenyl. In yet another example,when ring A is thiophen, then Z is other than oxadiazole, wherein theoxadiazole is substituted with a phenyl, 4-methyl-phenyl, or a4-ethyl-phenyl group. In another example, when ring A is methyl- orethyl-substituted thiophene, then Z is other than oxadiazole.

In another example, when ring A is thiophene, then Z is other thanpyrimidinone. In another example, when ring A is thiophene, then Z isother than substituted pyrimidinone (e.g., pyrimidinone substituted withat least one of hydroxy, carboxy or hydroxy-methylene)

W

In another example according to any of the above embodiments of Formulae(I) to (IX), W is straight chain alkylene represented by—(CR¹⁰R¹¹)_(n)—, wherein n is chosen from 1 to 10 and R¹⁰ and R¹¹ aredefined as hereinbelow for Formulae (X) and (XI). In another example, Wis straight chain alkylene represented by —CH₂)_(n)—, wherein n ischosen from 1 to 10. In one embodiment, n is 1 or 2. In yet anotherexample according to any of the above embodiments of Formula (I) to(IX), W is unsubstituted methylene (—CH₂—).

The present disclosure further provides a compound having a structureaccording to Formula (X) or Formula (XI):

or a salt or solvate thereof, wherein Z, R⁵ and Cy are defined as forFormula (I) above.

In Formula (X) and Formula (XI), X¹ and X³ are independently chosen fromN and CR^(2a). R² and R^(2a) are each independently defined as R² inFormula (IIIa) and Formula (IIIb). In one example, R² and R^(2a) areindependently chosen from H, substituted or unsubstituted C₁-C₁₀ alkyl,substituted or unsubstituted 3- to 10-membered heterocycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted 3- to 8-membered membered heterocycloalkyl, substituted orunsubstituted aryl (e.g., phenyl), substituted or unsubstitutedheteroaryl (e.g., pyridyl), CN, halogen. In another example, R² andR^(2a) are independently chosen from H, C₁-C₄ alkyl (e.g., methyl,ethyl, iso-propyl, tert-butyl), C₃-C₆ cycloalkyl (e.g., cyclopropyl),C₁-C₄ haloalkyl (e.g., CF₃, CHF₂, CH₂F, CH₂CF₃), halogen (e.g., F, Cl orBr) and CN. In one example, R² and R^(2a) are independently chosen fromH, methyl, halogen and CN.

In Formula (X) and Formula (XI), R¹⁰ and R¹¹ are independently chosenfrom H, substituted or unsubstituted alkyl (e.g., C₁-C₆-alkyl),substituted or unsubstituted alkenyl (e.g., C₁-C₆-alkenyl), substitutedor unsubstituted alkynyl (e.g., C₁-C₆-alkynyl), haloalkyl (e.g.,C₁-C₆-haloalkyl), substituted or unsubstituted heteroalkyl (e.g., 2- to6-membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g.,C₃-C₆-cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.,3- to 8-membered heterocycloalkyl), substituted or unsubstituted aryl(e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., 5- or6-membered heteroaryl), CN, halogen, OR⁴², SR⁴², NR⁴²R⁴³, C(O)R⁴⁴,C(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³, C(O)OR⁴², NR⁴⁵C(O)R⁴⁴, NR⁴⁵C(O)OR⁴²,NR⁴⁵C(O)NR⁴²R⁴³, NR⁴⁵C(S)NR⁴²R⁴³, NR⁴⁵S(O)₂R⁴⁴, S(O)₂NR⁴²R⁴³, S(O)R⁴⁴and S(O)₂R⁴⁴, wherein R⁴², R⁴³ and R⁴⁵ are independently chosen from H,acyl, C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl,wherein R⁴² and R⁴³, together with the nitrogen atom to which they arebound are optionally joined to form a 5- to 7-membered heterocyclicring. R⁴⁴ is independently chosen from acyl, C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- to 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl. In one example, R¹⁰and R¹¹ are both H.

In Formula (X) and Formula (XI), Z is chosen from those Z-groupsdescribed herein, above. In one example, Z in Formula (X) or Formula(XI) is chosen from:

wherein n, m, o, Y⁵, R⁴, R^(4a), and R¹⁶ are defined as hereinabove. Inanother example, Z in Formula is a triazole.

Substituent R⁵

In any of the embodiments of Formula (I) to (XI), R⁵ is defined as forFormula (I). In one example, according to any of the above embodimentsof Formulae (I) to (XI), R⁵ is H or C₁-C₃ alkyl. In another example,according to any of the above embodiments of Formulae (I) to (XI), R⁵ isH. In another example according to any of the above embodiments ofFormula (I) to (XI), R⁵ is H and W is methylene (—CH₂—).

In one example, the compounds of the present disclosure have a structureaccording to Formula (XII), Formula (XIII), Formula (XIV) or Formula(XV):

or a tautomer, mixture of tautomers, salt or solvate thereof, wherein Cyand R⁴ are defined as for Formula (I) hereinabove. R² and R^(2a) aredefined as for Formulae (IV) to (VII) hereinabove. In one example in theabove structures, R² and R^(2a) (when present) are independently chosenfrom H, halogen (e.g., F, Cl, Br), methyl and halogen-substituted methyl(e.g., CF₃ or CHF₂). In another example, R⁴ is H or methyl. In yetanother example, R² and R^(2a) (when present) are independently H,halogen (e.g., F, Cl, Br) or halogen-substituted methyl, and R⁴ is H ormethyl.

Ring Cy

Cy in any of the embodiments of Formula (I) to (XV) represents a ring ora fused ring system. In one example according to any of the aboveembodiments of Formula (I) to (XV), Cy is chosen from substituted orunsubstituted C₃-C₁₂ cycloalkyl (e.g., substituted or unsubstitutedcyclopentane, cyclohexane, norbornane or adamantane), substituted orunsubstituted 3- to 12-membered heterocycloalkyl (e.g., substituted orunsubstituted morpholino), substituted or unsubstituted aryl (e.g.,substituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl), substituted or unsubstituted heteroaryl (e.g., substituted orunsubstituted pyridyl, substituted or unsubstituted quinoline,substituted or unsubstituted isoquinoline, substituted or unsubstitutedquinoxaline, substituted or unsubstituted quinazoline) and other fusedring systems (e.g., substituted or unsubstituted3,4-dihydroquinolin-2-one, and substituted or unsubstituted3,4-dihydro-1,6-naphthyridin-2-one). In one example, each of the abovecycloalkyl, heterocycloalkyl, aryl or heteroaryl groups is optionallysubstituted with from 1to 8 R²⁰ groups, wherein each R²⁰ isindependently chosen from substituted or unsubstituted alkyl (e.g.,C₁-C₆-alkyl), substituted or unsubstituted alkenyl (e.g.,C₁-C₆-alkenyl), substituted or unsubstituted alkynyl (e.g.,C₁-C₆-alkynyl), haloalkyl (e.g., C₁-C₆-haloalkyl), substituted orunsubstituted heteroalkyl (e.g., 2- to 6-membered heteroalkyl),substituted or unsubstituted cycloalkyl C₃-C₆-cycloalkyl), substitutedor unsubstituted heterocycloalkyl (e.g., 3- to 8-memberedheterocycloalkyl), substituted or unsubstituted aryl (e.g., phenyl),substituted or unsubstituted heteroaryl (e.g., 5- or 6memberedheteroaryl), CN, halogen, OR⁵², SR⁵², NR⁵²R⁵³, C(O)R⁵⁴, C(O)NR⁵²R⁵³,OC(O)NR⁵²R⁵³, C(O)OR⁵², NR⁵⁵C(O)R⁵⁴, NR⁵⁵C(O)OR⁵², NR⁵⁵C(O)NR⁵²R⁵³,NR⁵⁵C(S)NR⁵²R⁵³, NR⁵⁵S(O)₂R⁵⁴, S(O)₂NR⁵²R⁵³, S(O)R⁵⁴ and S(O)₂R⁵⁴,wherein R⁵², R⁵³ and R⁵⁵ are independently chosen from H, acylC₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl,wherein R⁵² and R⁵³, together with the nitrogen atom to which they arebound are optionally joined to form a 5- to 7-membered heterocyclicring. R⁵⁴ is independently chosen from acyl, C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- to 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl.

In one example, Cy in any of the above embodiments of Formula (I) to(XV) has a structure chosen from:

wherein q is an integer chosen from 0 to 5, r is an integer chosen from0 to 4, s is an integer chosen from 0 to 6, t is an integer chosen from0 to 8 and each R²⁰ is independently defined as above. At least two R²⁰,together with the atoms to which they are attached, are optionallyjoined to form a 5- to 7-membered ring. In one example, two R²⁰,together with the atoms to which they are attached, are joined to form a5- or 6-membered, aromatic (e.g., phenyl) or heteroaromatic (e.g.,pyridyl, pyrimidyl, pyrazyl, thienyl or pyrazole) ring.

In a further example, Cy in any of the above embodiments of Formula (I)to (XV) is 4-substituted or 3-substituted phenyl or pyridyl. Forexample, Cy has a structure chosen from:

wherein u is an integer chosen from 0 to 4, v is an integer chosen from0 to 3. R²⁰ is defined as herein above. In one example, R²⁰ in the abovestructures is OR⁵¹, wherein R⁵¹ is defined as herein above. In oneexample, R⁵¹ is chosen from substituted or unsubstituted alkyl (e.g.,C₁-C₆ alkyl). In one embodiment, R²⁰ in the above structures is chosenfrom methoxy and ethoxy. Each R^(20a) in the above structures isindependently chosen from R²⁰ groups as defined herein above. In oneexample, the integer u or the integer v are 0 and R^(20a) in the abovestructures is absent.

In a further example, Cy in any of the above embodiments of Formula (I)to (XV) is chosen from:

wherein R²⁰ and R^(20a) are defined as herein above. R²⁰ and R^(20a),together with the atoms to which they are attached, are optionallyjoined to form a 5- to 7-membered ring.

In yet another example, Cy in any of the above embodiments of Formula(I) to (XV) is chosen from:

wherein v is an integer chosen from 0 to 3, w is an integer chosen form0 to 2, x is an integer chosen from 0 to 4, and y is an integer chosenfrom 0 to 2. Each R^(20a) in the above structures is independentlychosen and is defined as herein above. In one example, each R^(20a) inthe above structures is absent, Y⁶, Y⁷, Y⁸ and Y⁹ are independentlychosen from N and CR^(20b), wherein each R^(20b) is independently chosenfrom H and R²⁰ as defined herein above. In one example, Y⁶, Y⁷, Y⁸ andY⁹ are chosen from N and CH. Y¹⁰ is a chosen from O and S. In anotherexample, Y¹⁰ is S.

In a further example, Cy in any of the above embodiments of Formula (I)to (XV) is chosen from:

wherein v, x, R^(20a) and R^(20b) are defined as herein above. Theinteger z is chosen from 0 to 4 and the integer a is chosen form 0 to 3.In one example in the above structures R^(20a) is absent. In anotherexample, each R^(20b) in the above structures is H. In yet anotherexample in the above structures, each R^(20a) is absent from eachR^(20b) is H.

In Vitro Activities

Certain compounds of the present disclosure exhibit various in vitrobiological activities as demonstrated, e.g., in Example 14 and FIG. 1.For example, certain compounds of the present disclosure exhibitinhibitory activity against Jun N-terminal kinases (JNKs). In vitroassays for the determination of JNK activities are known in the art andexemplary assay formats are described herein (see e.g., Example 14).Many compounds of the present disclosure are especially active againstJNK3 (e.g., aJNK3 or cJNK3) but may also inhibit JNK1 and JNK2.

In one example, the compounds of the present disclosure may beinhibitors of aJNK3 with an IC₅₀ of less than about 50 μM, less thanabout 40 μM, less than about 30 μM, less than about 20 μM or less thanabout 10 μM. In another example, the compounds of the present disclosuremay exhibit inhibitory activity against a JNK3 with an IC₅₀ of less thanabout 9 μM, less than about 8 μM, less than about 7 μM, less than about6 μM, less than about 5 μM, less than about 4 μM, less than about 3 μM,less than about 2 μM, or less than about 1 μM. In yet another example,the compounds of the present disclosure may exhibit inhibitory activityagainst a JNK3 with an IC₅₀ of less than about 0.9 μM, less than about0.8 μM, less than about 0.7 μM, less than about 0.6 μM, less than about0.5 μM, less than about 0.4 μM, less than about 0.3 μM, less than about0.2 μM. For example, the compounds of the present disclosure may exhibitinhibitory activity against a JNK3 with an IC₅₀ of less than about 0.1μM (100 nM). In another example, the compounds of the present disclosuremay exhibit inhibitory activity against a JNK3 with an IC₅₀ of less thanabout 90 nM, less than about 80 nM, less than about 70 nM, less thanabout 60 nM, less than about 50 nM, less than about 40 nM, less thanabout 30 nM or less than about 20 nM. In another example, the compoundsof the present disclosure may exhibit inhibitory activity against a JNK3with an IC₅₀ of less than about 10 nM.

Certain compounds of the present disclosure do not only exhibitinhibitory activity against JNK, but at the same time have little or noinhibitory activity against certain other members of the MAP kinasefamily of proteins. For example, certain compounds of the presentdisclosure are active against aJNK3 and show little or no inhibitoryactivity against p38 and/or MAPK. For the purpose of this applicationthe selectivity of the instant compounds for JNK over other kinases isexpressed in a ratio of IC₅₀ values. Those can be determined usingassays known in the art or those described herein (see e.g., Example14).

Certain compounds of the present disclosure are characterized by thefollowing inhibitory activities involving aJNK3 and p38. In one example,the ratio of IC₅₀ (aJNK3)/IC₅₀ (p38) is less than about 1, less thanabout 0.9, less than about 0.8, less than about 0.7, less than about0.6, less than about 0.5, less than about 0.4, less than about 0.3, lessthan about 0.2 or less than about 0.1. In another example, the ratio ofIC₅₀ (aJNK3)/IC₅₀ (p38) is less than about 0.09, less than about 0.08,less than about 0.07, less than about 0.06, less than about 0.05, lessthan about 0.04, less than about 0.03, less than about 0.02 or less thanabout 0.01. In a further example, the ratio of IC₅₀ (aJNK3)/IC₅₀ (p38)is less than 0.009, less than about 0.008, less than about 0.007, lessthan about 0.006, less than about 0.005, less than about 0.004, lessthan about 0.003, less than about 0.002 or less than about 0.001. In yetanother example, the ratio of IC₅₀ (aJNK3)/IC₅₀ (p38) is less than about0.0009, less than about 0.0008, less than about 0.0007, less than about0.0006, less than about 0.0005, less than about 0.0004, less than about0.0003, less than about 0.0002 or less than about 0.0001.

Certain compounds of the present disclosure are characterized by thefollowing inhibitory activities involving aJNK3 and MAPK. In oneexample, the ratio of IC₅₀ (aJNK3)/IC₅₀ (MAPK) is less than about 1,less than about 0.9, less than about 0.8, less than about 0.7, less thanabout 0.6, less than about 0.5, less than about 0.4, less than about0.3, less than about 0.2 or less than about 0.1. In another example, theratio of IC₅₀ (aJNK3)/IC₅₀ (MAPK) is less than about 0.09, less thanabout 0.08, less than about 0.07, less than about 0.06, less than about0.05, less than about 0.04, less than about 0.03, less than about 0.02or less than about 0.01. In a further example, the ratio of IC₅₀(aJNK3)/IC₅₀ (MAPK) is less than 0.009, less than about 0.008, less thanabout 0.007, less than about 0.006, less than about 0.005, less thanabout 0.004, less than about 0.003, less than about 0.002 or less thanabout 0.001. In yet another example, the ratio of IC₅₀ (aJNK3)/IC₅₀(MAPK) is less than about 0.0009, less than about 0.0008, less thanabout 0.0007, less than about 0.0006, less than about 0.0005, less thanabout 0.0004, less than about 0.0003, less than about 0.0002 or lessthan about 0.0001.

Certain compounds of the present disclosure are characterized by thefollowing inhibitory activities involving aJNK3, p38 and MAPK. In oneexample, the ratio of IC₅₀ (aJNK3)/IC₅₀ (MAPK) and the ratio of IC₅₀(aJNK3)/IC₅₀ (p38) is each less than about 1, less than about 0.9, lessthan about 0.8, less than about 0.7, less than about 0.6, less thanabout 0.5, less than about 0.4, less than about 0.3, less than about 0.2or less than about 0.1. In another example, the ratio of IC₅₀(aJNK3)/IC₅₀ (MAPK) and the ratio of IC₅₀ (aJNK3)/IC₅₀ (p38) is eachless than about 0.09, less than about 0.08, less than about 0.07, lessthan about 0.06, less than about 0.05, less than about 0.04, less thanabout 0.03, less than about 0.02 or less than about 0.01. In a furtherexample, the ratio of IC₅₀ (aJNK3)/IC₅₀ (MAPK) and the ratio of IC₅₀(aJNK3)/IC₅₀ (p38) is each less than about 0.009, less than about 0.008,less than about 0.007, less than about 0.006, less than about 0.005,less than about 0.004, less than about 0.003, less than about 0.002 orless than about 0.001. In yet another example, the ratio of IC₅₀(aJNK3)/IC₅₀ (MAPK) and the ratio of IC₅₀ (aJNK3)/IC₅₀ (p38) is eachthan about 0.0009, less than about 0.0008, less than about 0.0007, lessthan about 0.0006, less than about 0.0005, less than about 0.0004, lessthan about 0.0003, less than about 0.0002 or less than about 0.0001.

Exemplary compounds of the present disclosure and their in vitrobiological activities are listed in Table 1, below. IC₅₀ values in Table1 were determined using the procedures of Example 14.

TABLE 1 In Vitro Biological Activities JNK3 JNK1 JNK2 Compound Name IC₅₀(μM) IC₅₀ (μM) IC₅₀ (μM) N-(2-(1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(++) (++) (++) (naphthalen-1-yl)acetamideN-(2-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2- (++) (++) (++)(naphthalen-1-yl)acetamideN-(2-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)thiophen-3- (+) (+) (−)yl)-2-(naphthalen-1-yl)acetamideN-(2-(1-methyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2- (−) (−) (−)(naphthalen-1-yl)acetamide2-(4-methoxyphenyl)-N-(2-(3-methyl-1H-1,2,4-triazol- (++) (++) (++)5-yl)thiophen-3-yl)acetamideN-(2-(1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(4- (++) (++) (++)methoxyphenyl)acetamide N-(2-(1H-1,2,4-triazol-1-yl)thiophen-3-yl)-2-(4-(+) (+) (−) methoxyphenyl)acetamide2-(4-methoxyphenyl)-N-(4-methyl-3-(3-methyl-1H- (++) (++) (++)1,2,4-triazol-5-yl)thiophen-2-yl)acetamideN-(2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)-2-(4- (++) (++) (++)methoxyphenyl)acetamideN-(2-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)thiophen-3- (++) (++) (++)yl)-2-(4-methoxyphenyl)acetamideN-(2-(3-ethyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(4- (++) (++) (++)methoxyphenyl)acetamideN-(2-(3-tert-butyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)- (++) (++) (+)2-(4-methoxyphenyl)acetamide2-(4-methoxyphenyl)-N-(2-(3-(tetrahydrofuran-2-yl)- (++) (++) (++)1H-1,2,4-triazol-5-yl)thiophen-3-yl)acetamide2-(4-methoxyphenyl)-N-(2-(3-(trifluoromethyl)-1H- (++) (++) (+)1,2,4-triazol-5-yl)thiophen-3-yl)acetamideN-(4-methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (++)-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide (+++)N-(4-methyl-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2- (+++) (+++)(+++) yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide2-(4-methoxyphenyl)-N-(2-(3-(pyridin-4-yl)-1H-1,2,4- (+) (++) (−)triazol-5-yl)thiophen-3-yl)acetamideN-(2-(3-amino-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2- (++) (++) (++)(4-methoxyphenyl)acetamideN-(4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamideN-(3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4- (++) (+++) (++)dihydroquinolin-1(2H)-yl)acetamideN-(4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(isoquinolin-5-yl)acetamideN-(4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(quinolin-5-yl)acetamideN-(2-(1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(2,3- (++) (++) (++)dihydrobenzo[b][1,4]dioxin-6-yl)acetamideN-(4-methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (++) (++) (++)(quinolin-5-yl)acetamide2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(2-(3- (++) (++) (++)methyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)acetamideN-(2-(1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(quinolin- (++) (++) (++)5-yl)acetamide N-(4-methyl-3-(3-methyl-1H-1,2,4-triazol-5- (+++) (+++)(++) yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamideN-(4-methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (++) (++) (++)(quinoxalin-5-yl)acetamide N-(4-methyl-3-(3-methyl-1H-1,2,4-triazol-5-(++) (++) (++) yl)thiophen-2-yl)-2-(quinoxalin-5-yl)acetamideN-(4-methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (++) (++) (++)(4-(3-(piperidin-1-yl)propoxy)phenyl)acetamideN-(4-methyl-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)- (++) (++)(++) 2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetamide2-(4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)-N-(4-methyl- (++) (++) (++)3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(isoquinolin-5-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(quinolin-5-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamideN-(4-cyano-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(isoquinolin-5-yl)acetamideN-(4-cyano-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamideN-(2-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2- (++) (++) (++)(4-(2-oxopyrrolidin-1-yl)phenyl)acetamideN-(4-methyl-3-(5-methyl-4H-1,2,4-triazol-3- (++) (++) (++)yl)thiophen-2-yl)-2-(4-(pyridin-4-yl)phenyl)acetamideN-(4-cyano-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(quinolin-5-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-7-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(6-fluoro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(7-fluoro-2-oxoquinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(7-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(6,7-difluoro-2-oxoquinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(6-fluoro-2-oxoquinolin-1(2H)-yl)acetamide2-(isoquinolin-5-yl)-N-(2-(4-methylthiazol-2- (++) (++) (++)yl)thiophen-3-yl)acetamide2-(isoquinolin-5-yl)-N-(2-(thiazol-4-yl)thiophen-3- (++) (++) (++)yl)acetamide 2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)-N-(2- (++)(++) (++) (thiazol-4-yl)thiophen-3-yl)acetamide2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)-N-(2-(thiazol-4- (++) (++) (++)yl)thiophen-3-yl)acetamide2-(isoquinolin-5-yl)-N-(2-(2-methoxythiazol-4- (++) (++) (+)yl)thiophen-3-yl)acetamide N-(2-(2-chlorothiazol-4-yl)thiophen-3-yl)-2-(++) (++) (+) (isoquinolin-5-yl)acetamide2-(isoquinolin-5-yl)-N-(2-(thiazol-2-yl)thiophen-3- (++) (++) (++)yl)acetamide 2-(isoquinolin-5-yl)-N-(2-(5-methylthiazol-2- (++) (++)(++) yl)thiophen-3-yl)acetamide2-(4-(3-(piperidin-1-yl)propoxy)phenyl)-N-(2-(thiazol- (++) (++) (++)4-yl)thiophen-3-yl)acetamideN-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-2- (++) (++) (+)(isoquinolin-5-yl)acetamide2-(4-methoxyphenyl)-N-(2-(oxazol-2-yl)thiophen-3- (++) (++) (+)yl)acetamide 2-(isoquinolin-5-yl)-N-(2-(oxazol-2-yl)thiophen-3- (++)(++) (++) yl)acetamide2-(4-methoxyphenyl)-N-(3-(5-methyl-1,2,4-oxadiazol-3- (++) (++) (++)yl)thiophen-2-yl)acetamide N-(2-(1,3,4-oxadiazol-2-yl)thiophen-3-yl)-2-(++) (++) (+) (naphthalen-1-yl)acetamide2-(4-methoxyphenyl)-N-(2-(5-methyl-1,3,4-oxadiazol-2- (++) (++) (−)yl)thiophen-3-yl)acetamideN-(2-(5-isopropyl-1,3,4-oxadiazol-2-yl)thiophen-3-yl)- (+) (+) (−)2-(4-methoxyphenyl)acetamideN-(2-(5-methyl-1,3,4-oxadiazol-2-yl)thiophen-3-yl)-2- (++) (++) (+)(naphthalen-1-yl)acetamideN-(4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)thiophen- (++) (++) (++)2-yl)-2-(naphthalen-1-yl)acetamideN-(4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)thiophen- (++) (++) (++)2-yl)-2-(4-(pyridin-4-yl)phenyl)acetamideN-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thiophen-3-yl)-2- (++) (++) (−)(naphthalen-1-yl)acetamideN-(4-(1H-1,2,4-triazol-5-yl)thiazol-5-yl)-2-(isoquinolin- (++) (++) (++)5-yl)acetamide 2-(isoquinolin-5-yl)-N-(4-(1-methyl-1H-1,2,4-triazol-5-(++) (++) (++) yl)thiazol-5-yl)acetamide2-(2-pyridyl)-3-(1-naphthylacetylamino)thiophene (++)N-(2-(1H-pyrazol-1-yl)thiophen-3-yl)-2-(4- (+) (+) (−)methoxyphenyl)-acetamide2-(4-methoxyphenyl)-N-(2-(4-methyl-1H-pyrazol-1- (+) (+) (+)yl)thiophen-3-yl)acetamideN-(2-(1H-pyrazol-3-yl)thiophen-3-yl)-2-(naphthalen-1- (++) (++) (−)yl)acetamide N-(2-(1-methyl-1H-pyrazol-3-yl)thiophen-3-yl)-2- (+) (+)(−) (naphthalen-1-yl)acetamideN-(2-(5-methyl-1H-pyrazol-3-yl)thiophen-3-yl)-2- (++) (++) (−)(naphthalen-1-yl)acetamide N-(3-(2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-(++) (++) (+) methoxyphenyl)-acetamide2-(4-methoxyphenyl)-N-(3-(2-methyl-2H-tetrazol-5- (++) (++) (+)yl)thiophen-2-yl)acetamideN-(3-(2-(methoxymethyl)-2H-tetrazol-5-yl)thiophen-2- (−) (−) (−)yl)-2-(4-methoxyphenyl)acetamideN-(3-(1-(methoxymethyl)-1H-tetrazol-5-yl)thiophen-2- (++) (++) (−)yl)-2-(4-methoxyphenyl)acetamideN-(2-(1-methyl-1H-imidazol-2-yl)thiophen-3-yl)-2- (+) (+) (−)(naphthalen-1-yl)acetamide2-(4-methoxyphenyl)-N-(2-(1-methyl-1H-imidazol-4- (+) (+) (−)yl)thiophen-3-yl)acetamide N-(2-(1H-imidazol-4-yl)thiophen-3-yl)-2-(4-(+) (+) (−) methoxyphenyl)-acetamideN-(2-(1H-imidazol-4-yl)thiophen-3-yl)-2-(2-oxo-3,4- (++) (++) (+)dihydroquinolin-1(2H)-yl)acetamide2-(4-methoxyphenyl)-N-(2-(2-methyl-1H-imidazol-4- (+) (+) (−)yl)thiophen-3-yl)acetamideN-(2-(2-methyl-1H-imidazol-4-yl)thiophen-3-yl)-2-(2- (+) (+) (−)oxo-3,4-dihydroquinolin-1(2H)-yl)acetamideN-(2-(1H-imidazol-1-yl)thiophen-3-yl)2-(naphthalen-1- (++) (+) (−)yl)acetamide 2-(4-methoxyphenyl)-N-(2-(4-methyl-1H-imidazol-1- (−) (−)(−) yl)thiophen-3-yl)acetamide2-(4-methoxyphenyl)-N-(2-(pyrazin-2-yl)thiophen-3- (++) (++) (++)yl)acetamide 2-(isoquinolin-5-yl)-N-(4-(pyrazin-2-yl)thiazol-5- (++)(++) (++) yl)acetamideN-(4,4′-bithiazol-5-yl)-2-(isoquinolin-5-yl)acetamide (+++) (+++) (++)2-(4-methoxyphenyl)-N-(2-(2-oxooxazolidin-3- (+) (−) (−)yl)thiophen-3-yl)acetamide2-(7-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)-N-(4- (++) (++) (++)bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)acetamideN-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (+++) (+++) (++)(quinolin-4-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(8-fluoroisoquinolin-5-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-1,6-naphthyridin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (++)(8-fluoroquinolin-5-yl)acetamideN-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (++) (++) (++)(7-(trifluoromethyl)quinolin-5-yl)acetamideN-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (++) (++) (++)(5-(trifluoromethyl)quinolin-7-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-1,5-naphthyridin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(6-chloro-2-oxoquinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(5-fluoro-2-oxoquinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (++) (+++) (++)(3-fluoroquinolin-8-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetamideN-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (+++) (+++) (++)(isoquinolin-4-yl)acetamideN-(5-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (++) (+++) (++)(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(3-fluoroquinolin-5-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(7-cyano-2-oxoquinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (++)(isoquinolin-8-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(6-cyano-2-oxoquinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (++) (++)(quinolin-8-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (++)(2-oxo-5-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-6-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)- yl)acetamideN-(4-cyano-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen- (+++) (+++) (+++)2-yl)-2-(quinolin-5-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (++) (++) (++)(2-(trifluoromethyl)quinolin-7-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (++)(7-fluoroquinolin-5-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (+++) (+++) (++)(3-(trifluoromethyl)quinolin-5-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(6-fluoroquinolin-5-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (++) (+++) (++)(6-fluoroquinolin-7-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(6-ethynyl-2-oxoquinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-7-(trifluoromethyl)-1,6-naphthyridin-1(2H)- yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (++) (++) (++)(3-(trifluoromethyl)quinolin-8-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (++) (+++) (++)(6-methylimidazo[2,1-b]thiazol-3-yl)acetamide2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)-N-(2- (+++) (+++) (++)(thiazol-4-yl)thiophen-3-yl)acetamideN-(4-cyano-3-(pyrazin-2-yl)thiophen-2-yl)-2-(quinolin- (+++) (+++) (++)5-yl)acetamide 2-(2-oxo-1,6-naphthyridin-1(2H)-yl)-N-(2-(thiazol-4- (++)(+++) (++) yl)thiophen-3-yl)acetamideN-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (++) (+++) (++)(3,3-difluoro-2-oxoindolin-1-yl)acetamide2-(benzo[d]thiazol-7-yl)-N-(4-bromo-3-(1H-1,2,4- (+++) (+++) (++)triazol-5-yl)thiophen-2-yl)acetamideN-(4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-cyano-3-(oxazol-2-yl)thiophen-2-yl)-2-(2-oxo-6- (+++) (+++) (+++)(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2- (+++) (+++)(+++) oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetamideN-(3-(1,2,4-oxadiazol-3-yl)thiophen-2-yl)-2-(6,7- (++) (+++) (++)difluoro-2-oxoquinolin-1(2H)-yl)acetamideN-(4-cyano-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-6- (+++) (+++) (+++)(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(5-oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin- 4(5H)-yl)acetamideN-(4-cyano-3-(thiazol-4-yl)thiophen-2-yl)-2-(2-oxo-6- (+++) (+++) (+++)(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (++) (+++) (++)(imidazo[1,2-a]pyridin-5-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7- (+++) (+++)(+++) fluoro-2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (+++)(+++) (+++) (2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamideN-(4-cyano-3-(thiazol-5-yl)thiophen-2-yl)-2-(2-oxo-6- (++) (++) (++)(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-cyano-3-(1H-1,2,3-triazol-1-yl)thiophen-2-yl)-2- (++) (++) (++)(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(3-(1H-benzo[d][1,2,3]triazol-1-yl)-4-cyanothiophen-2-yl)- (++) (++)(++) 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(6-fluoroisoquinolin-5-yl)acetamide; and N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroisoquinolin-7-yl)acetamideN-(4-cyano-3-(2H-1,2,3-triazol-2-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2- (+++) (+++)(+++) oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamideN-(4-cyano-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4- (+++) (+++)(+++) dihydro-1,5-naphthyridin-1(2H)-yl)acetamideN-(4-chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2- (+++) (+++)(+++) yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamideN-(4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamideN-(4-bromo-3-(oxazol-2-yl)thiophen-2-yl)-2-(2-oxo- (+++) (+++) (+++)3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamideN-(4-bromo-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo- (+++) (+++) (++)3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamideN-(4-chloro-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo- (+++) (+++) (+++)3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamideN-(3-(benzo[d]thiazol-2-yl)-4-cyanothiophen-2-yl)-2-(2- (++) (++) (++)oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamideN-(4-chloro-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)- (+++)(+++) (+++) 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamideN-(4-chloro-3-(1-(3-(dimethylamino)propyl)-1H-1,2,4- (+++) (+++) (+++)triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-chloro-3-(1-(3-(4-methylpiperazin-1-yl)propyl)- (+++) (+++) (++)1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-chloro-3-(3-ethyl-1H-1,2,4-triazol-5-yl)thiophen- (+++) (+++) (++)2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)- yl)acetamideN-(4-chloro-3-(1-(2-(dimethylamino)ethyl)-1H-1,2,4- (+++) (+++) (+++)triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-N- (++) (++) (++)(2-(dimethylamino)ethyl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-cyano-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamideN-(4-chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen- (+++) (+++)(+++) 2-yl)-2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamideN-(4-chloro-3-(1-(3-morpholinopropyl)-1H-1,2,4- (+++) (+++) (+++)triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (++) (++) (++)(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)-N-(3-(pyrrolidin-1-yl)propyl)acetamideN-(4-chloro-3-(1-(3-(pyrrolidin-1-yl)propyl)-1H-1,2,4- (+++) (+++) (+++)triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen- (+++) (+++)(+++) 2-yl)-2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetamideN-(4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (++) (+++) (++)(8-(trifluoromethyl)quinolin-5-yl)acetamideN-(4-bromo-3-(2H-1,2,3-triazol-2-yl)thiophen-2-yl)-2- (+++) (+++) (++)(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamideN-(4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo- (+++)(+++) (+++) 6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetamideN-(4-chloro-3-(3-isopropyl-1H-1,2,4-triazol-5- (++) (+++) (++)yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide2-(6-bromo-2-oxoquinolin-1(2H)-yl)-N-(4-bromo-3- (+++) (+++) (+++)(1H-1,2,4-triazol-3-yl)thiophen-2-yl)acetamideN-(4-cyano-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen- (+++) (+++) (+++)2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)- yl)acetamide2-(6-bromo-2-oxoquinolin-1(2H)-yl)-N-(4-chloro-3- (+++) (+++) (+++)(1H-1,2,4-triazol-3-yl)thiophen-2-yl)acetamideN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(6-cyano-2-oxoquinolin-1(2H)-yl)acetamideN-(4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(5-oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin- 4(5H)-yl)acetamideN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2- (+++) (+++) (+++)(2-oxo-7-(trifluoromethyl)-1,6-naphthyridin-1(2H)- yl)acetamideN-(4-chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen- (+++) (+++)(+++) 2-yl)-2-(5-oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamideN-(4-chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen- (+++) (+++)(+++) 2-yl)-2-(2-oxo-7-(trifluoromethyl)-1,6-naphthyridin-1(2H)-yl)acetamide (+++) IC₅₀ < 0.1 μM (++) IC₅₀ 0.1 μM-10 μM (+) IC₅₀ >10 μM (−) Activity below level of detection in assay used (IC₅₀ > 50 μM)

In Vivo Activities

Certain compounds of the present disclosure exhibit in vivo biologicalactivities, such as the inhibition of excitotoxic cell death. An in vivomodel, which can be used to assess the potential in vivo beneficialeffect of the compounds of the present disclosure is described inExample 15. Excitotoxic cell death can be induced experimentally by theadministration of kainic acid. Peripheral injection of kainic acidresults in the degeneration of neurons in the hippocampus. Mice lackingthe Jnk3 gene are resistant to kainic acid-induced upregulation ofphosphorylated c-jun (p-cjun) and hippocampal neuronal apotosis (seee.g., Yang D. D. et al., Nature 1997, 389: 865-870). Phosphorylatedc-jun in wildtype mice is upregulated after kainic acid administrationand demonstrate that this upregulation is inhibited by certain compoundsof the present disclosure.

Certain compounds of the present disclosure are characterized by thefollowing in vivo biological activities involving the concentration ofp-cjun in the brain tissue (e.g., hippocampus) of a test animal (e.g.,rodent, such as mice, rat, rabbit and the like) after treatment of thetest animal with an excitatory amino acid or analog thereof (e.g.,kainic acid). In one example, administration of a compound of thepresent disclosure to a test animal (e.g., at a dose of at least about100, 200 or 300 mg/kg), results in a reduction of kainic acid-inducedp-cjun concentration in the brain tissue of the test animal by at leastabout 1%, at least about 2%, at least about 3%, at least about 4%, atleast about 5%, at least about 6%, at least about 7%, at least about 8%,at least about 9% or at least about 10% relative to the p-cjunconcentration found in brain tissue of a comparable, untreated (vehicletreated) test animal. In another example, administration of a compoundof the present disclosure to a test animal (e.g., at a dose of at leastabout 100, 200 or 300 mg/kg), results in a reduction of kainicacid-induced p-cjun concentration in the brain tissue of the test animalby at least about 11%, at least about 12%, at least about 13%, at leastabout 14%, at least about 15%, at least about 16%, at least about 17%,at least about 18%, at least about 19% or at least about 20%, relativeto the p-cjun concentration found in brain tissue of a comparable,untreated (vehicle treated) test animal. In yet another example,administration of a compound of the present disclosure to a test animal(e.g., at a dose of at least about 100, 200 or 300 mg/kg), results in areduction of kainic acid-induced p-cjun concentration in the braintissue of the test animal by at least 21%, at least about 22%, at leastabout 23%, at least about 24%, at least about 25%, at least about 26%,at least about 27%, at least about 28 %, at least about 29% or at leastabout 30% relative to the p-cjun concentration found in brain tissue ofa comparable, untreated (vehicle treated) test animal. In a furtherexample, administration of a compound of the present disclosure to atest animal at a dose of at least about (100, 200 or 300 mg/kg), resultsin a reduction of kainic acid-induced p-cjun concentration in the braintissue of the test animal by at least about 31%, at least about 32%, atleast about 33%, at least about 34%, at least about 35%, at least about36%, at least about 37%, at least about 38%, at least about 39 or atleast about 40% relative to the p-cjun concentration found in braintissue of a comparable, untreated (vehicle treated) test animal. In yetanother example, administration of a compound of the present disclosureto a test animal (e.g., at a dose of at least about 100, 200 or 300mg/kg), results in a reduction of kainic acid-induced p-cjunconcentration in the brain tissue of the test animal by at least about41%, at least about 42%, at least about 43%, at least about 44%, atleast about 45%, at least about 46%, at least about 47 %, at least about48%, at least about 49% or at least about 50% relative to the p-cjunconcentration found in brain tissue of a comparable, untreated (vehicletreated) test animal. In yet another example, administration of acompound of the present disclosure to a test animal (e.g., at a dose ofat least about 300 mg/kg), results in a reduction of kainic acid-inducedp-cjun concentration in the brain tissue of the test animal by at leastabout 51%, at least about 52%, at least about 53%, at least about 54%,at least about 55%, at least about 56%, at least about 57%, at leastabout 58%, at least about 59% or at least about 60% relative to thep-cjun concentration found in brain tissue of a comparable, untreated(vehicle treated) test animal.

Synthesis of Compounds

The compounds of the present disclosure can be prepared using methodsknown in the art of organic synthesis and those described herein (see,e.g., Examples 1 to 13). The starting materials and variousintermediates may be obtained from commercial sources, prepared fromcommercially available compounds, and/or prepared using known syntheticmethods. For example, the compounds of the present disclosure, as wellas all intermediates, can be synthesized by known processes using eithersolution or solid phase techniques. Exemplary procedures for preparingcompounds of the present disclosure are outlined in the followingschemes.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and P. G. M. Wuts, Protecting Groups inOrganic Synthesis, Third Edition, Wiley, New York, 1999, and referencescited therein.

In one example, the compounds of the present disclosure are preparedusing a procedure outlined in Scheme 1a, below:

In Scheme 1a, Cy and W are defined as herein above. X¹ and X³ areindependently chosen from CR², S and N with the proviso that at leastone of X¹ and X³ is S. R² is as defined as herein above. R^(a) is chosenfrom substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl and substituted or unsubstituted heteroaryl. Inone example R^(a) in Scheme 1a is C₁-C₄ alkyl (e.g., methyl or ethyl).The moiety —C(O)E of compound II represents a carboxylic acid group (inwhich E is OH), an acid chloride (in which E is Cl) or an activatedester, such as a N-hydroxysuccinimide ester (NHS-ester) a carbodiimide,a triazolol and the like. The activated ester is optionally formed insitu from the corresponding acid, in which E is OH. In one example,compound III is formed by contacting compound I and compound II (whereinE is OH) in the presence of a coupling reagent and optionally an organicbase, such as an amine (e.g., diisopropylethyl amine, DIPEA). Couplingreagents suitable for amide bond formation are known to those of skillin the art and include dicyclohexylcarbodiimide (DCCI),diisopropylcarbodiimide (DIC), 1-hydroxybenzo-triazole (HOBT),1-hydroxy-7-aza-benzotriazole (HOAt), 6-chloro-1-hydroxybenzotriazole(Cl-HOBT), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDC),N-[(1H-benzotriazol-1-yl)dimethylamino)methylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HBTU),N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethlene]-N-methylmethanaminiumhexafluorophosphate (HATU),benzotriazol-1-yl-N-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate(PyBOP) and combinations thereof. Alternatively, POCl₃ and a base (e.g.,pyridine) can be used to form an amide bond.

After coupling, the ester group of compound III can be converted to ahetero-aromatic group Z. Exemplary groups Z are described herein above.Schemes 2 to 8 outline the formation of various Z groups. A person ofskill in the art will appreciate that the conversions shown in Schemes 2to 8 are exemplary and that compounds, which include other Z groups canbe synthesized using known methodologies and methods modified from thosepresented.

In one example, Z can be covalently linked to the core moiety via anaryl-aryl cross coupling reaction, such as a Suzuki or Stille-typereaction. An exemplary reaction is outline in Scheme 1b, below.

In Scheme 1b, Z, X¹, X³ and R² are as defined as herein above (see,e.g., Scheme 1a). X is halogen (e.g., Cl, Br or I). Y is a leaving groupsuitable for a cross-coupling reaction. In one example, Y is a leavinggroup suitable for a Stille-type cross-coupling reaction, e.g., atrialkylstannyl (e.g., tributylstannyl). In another example, Y is aleaving group suitable for a Suzuki-type cross-coupling reaction, e.g.,a boronic acid group. It is well within the capabilities of a skilledperson to select a suitable catalyst. Typically, the cross-couplingreaction will be palladium-catalyzed. However, other transition metalcatalysts can also be used. In one example, the catalyst is a palladiumphosphine, such as triphenyl phosphine, Pd(PPh₃)₄. In another example,the catalyst is a copper-based catalyst. The reducing agent can be anyreagent suitable for the reduction of a nitro group to an amino group.Exemplary reagents include hydrogen in combination with a metalcatalyst, such as palladium on carbon (Pd/C); and tin(II) reagents, suchas SnCl₂.

In Scheme 1b, the nitro analog is first coupled to Z, followed byreduction of the nitro group to an amino group. The resulting amine canthen be coupled to a suitable carboxylic acid derivative, e.g., asoutline in Scheme 1a. In another example, the coupling reaction isperformed after the amide has been formed as outlined in Scheme 1c,below.

In Scheme 1c, Z, Y, X¹, X³ and R², and the catalyst are defined asherein above (see, e.g., Scheme 1b).

In another example, the compounds of the present disclosure are preparedaccording to a procedure outlined in Scheme 1d, below:

In Scheme 1de, R², X¹ and X³ are defined as herein above and X is aleaving group, such as halogen (e.g., Cl, Br, I), tosylate, mesylate andthe like. Ring B represents any heterocyclic or heteroaromatic ring,(e.g., imidazole, pyrazole). Ring B can optionally be part of a largerring system (e.g., indolyl). In Scheme 1d, compound IIIb is reacted withcompound IVb, e.g., by heating the components in a suitable solvent,such as acetonitrile, to afford compound Vb. The nitro group of CompoundVb can then be reduced to an amino group, e.g., using a metal reducingagent, such as iron (Fe) or zinc to afford compound VIb. Compound VIbcan be further converted to a compound of the present disclosure bymeans of coupling with a suitable carboxylic acid or acid derivative,similarly to the reaction outlined in Scheme 1a.

Triazoles

In another example, the compounds of the present disclosure include atriazole moiety as the ring Z and are prepared using a procedureoutlined in Schemes 2a or 2b, below.

In Scheme 2a, the ester III is first converted to the hydrazide V (e.g.,using a hydrazine), which is further reacted with an imidamide (e.g.,acetimidamide or propionimidamide) in the presence of a base in order togive the triazole VII. In Scheme 2a, X¹, X³, R², R⁴, Cy and W aredefined as herein above. In one example, R⁴ is chosen from substitute orunsubstituted alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and amino (e.g., alkyl-amino). When R⁴ isamino, the imidamide reagent VI of Scheme 2a can be a guanidine. InScheme 2a, X¹ and X³ are independently chosen from C², S and N, with theproviso that at least one of X¹ and X³ is S. R² is defined as hereinabove.

Alternatively, the carboxylic acid IIIa can be converted to a primaryamide, which is then reacted with hydrazine to form a triazole, e.g., asoutlined in Scheme 2b, below:

In Scheme 2b, X¹, X³, R², Cy and W are defined as herein above.

Oxadizole

In another example, the compounds of the present disclosure include anoxadiazole moiety as the ring Z. Such compounds can be prepared usingprocedures outlined in Schemes 3a to 3e, below.

In Scheme 3a, X¹, X³, R², Cy and W are defined as herein above. InScheme 3a, the hydrazide V is reacted with trialkoxy-methane (e.g.,triethoxymethane) to form the 1,3,4-oxadizole analog VIII.

Alternatively, the carboxylic acid IIIa can be reacted with an acylhydrazide to prepare a substituted 1,3,4-oxadiazole analog VIIIa asoutlined in Scheme 3b, below.

In Scheme 3b, X¹, X³, R², Cy and W are defined as herein above.Alternatively, the unsubstituted oxadizole (R⁴=H in Formula VIIIa) canbe prepared by reacting the above carboxylic acid withisocyanoimino-triphenyl-phosphorane.

In Scheme 3c, X¹, X³, R², R^(a), Cy and W are defined as herein above.In Scheme 3c, the ester III is reacted with a hydroxyimidamide IX [e.g.,(E)-N′-hydroxyacetimidamide] to form the 1,2,4-oxadiazole analog X.

In Scheme 3d, X¹, X³, R², Cy and W are defined as herein above. InScheme 3d, the carboxylic acid IIIa, which can optionally be preparedthrough saponification of ester III, is first converted to the primaryamide XI (e.g., using ammonium hydroxide and a catalytic amount ofammonium chloride) and then further converted to the 1,2,4-oxadiazoleanalog XII, e.g., by means of N,N-dimethylformamide dimethyl acetal(DMF-DMA) followed by hydroxylamine.

In Scheme 3e, the nitrile IIIc, is first converted to the correspondingimidamide (e.g., using hydroxylamine), which is further reacted with anacid chloride (e.g., acetyl chloride) to give an oxadiazole. In Scheme3e, X¹, X³, R², R⁴, Cy and W are defined as herein above. In oneexample, R⁴ is C₁-C₄ alkyl (e.g., methyl).

Oxazole/Thiazole

In yet another example, the compounds of the present disclosure includean oxazole or a thiazole moiety as the ring Z and are prepared using aprocedure outlined in Scheme 4, below.

In Scheme 4, X¹, X³, R², R⁴, R^(4a), Cy, W and E are defined as hereinabove, e.g., for Scheme 1a. X is halogen (e.g., Cl, Br or I). In oneexample, X is Cl or Br. Y² is chosen from O and S. The catalyst can beany transition metal catalyst suitable for a Stille-type reaction. Inone example, the catalyst in Scheme 4 is a palladium catalyst, such as apalladium phosphine, e.g. palladium(0)tetrakistriphenylphosphine,Pd(PPh₃)₄.

In Scheme 4, the nitro analog XIII is first covalently linked to theoxazole or thiazole XIV. The nitro group of the resulting cross-coupledproduct XV is reduced to an amino group using an appropriate reducingagent, such as hydrogen in combination with a metal catalyst, such asPd/C. The reduced analog XVI can then he coupled to an appropriatecarboxylic acid analog, e.g., compound II, e.g., as outlined in Scheme1a, to produce the desired oxazole or thiazole.

A person of ordinary skill in the art will appreciate that compound XIVin Scheme 4 can be replaced with another oxazole, thiazole, isoxazole orisothiazole derivative to produce the corresponding products. Exemplaryreagents are:

wherein R⁴ is defined as hereinabove and Y² is O or S.

Imidazole

In a further example, the compounds of the present disclosure include animidazole moiety as the ring Z and are prepared using a relatedprocedure outlined in Scheme 5, below.

In Scheme 5, X¹, X³, R², R⁴, R^(4a)Cy, W and E are defined as hereinabove (see, e.g., Scheme 1a). X is halogen (e.g., Cl, Br or I). In oneexample, X is Cl or Br. The catalyst can be any transition metalcatalyst suitable for a Stille-type reaction. In one example, thecatalyst in Scheme 5 is a palladium catalyst, such as a palladiumphosphine, e.g. Pd(PPh₃)₄.

A person of ordinary skill in the art will appreciate that compound XVIIin Scheme 5 can be replaced with another imidazole derivative to producethe corresponding product. An exemplary reagent is:

wherein R³, R⁴ and R^(4a) are defined as hereinabove.

Alternatively, in Schemes 4 and 5, the coupling reaction with theimidazole, thiazole, oxazole and the like is performed subsequent to theamide formation, starting with compound XX. An exemplary couplingreaction is outlined below.

Tetrazole

In another example, the compounds of the present disclosure include atetrazole moiety as the ring Z. The tetrazole moiety can be preparedfrom the corresponding nitrile through reaction with anazido-trialkylstannane. An exemplary procedure is outlined in Scheme 6,below. For example, the nitrile XXI is reacted withazidotributylstannane (Bu₃SnN₃) to form the tetrazole XXII. Thetetrazole hydrogen can be replaced with another substituent (e.g., analkyl group) by contacting the tetrazole with an electrophile and,optionally, an organic or inorganic base (e.g., carbonate ortriethylamine). Exemplary electrophiles include X—R⁴, wherein R⁴ isdefined as herein above and X is a leaving group, such as halogen (e.g.,Cl, Br, I). In one example, X—R⁴ is a halogen-substituted alkyl orheteroalkyl reagents (e.g., MeI).

In Scheme 6, X¹, X³, R², R⁴, Cy and W are defined as herein above (see,e.g., Scheme 1a). R is alkyl (e.g., C₁-C₁₀ alkyl). A person of skill inthe art will appreciate that the tetrazole moiety can alternatively beformed prior to amide formation (e.g., starting with an appropriatecyano nitro analog).

Pyrazole

In another example, the compounds of the present disclosure include apyrazole moiety as the ring Z, and can be prepared using a proceduresoutline in Scheme 7, below.

In Scheme 7, X¹, X³, R², R⁴, R^(4a), Cy and W are defined as hereinabove (see, e.g., Scheme 1a). In one example, R⁴ is H or methyl. InScheme 7, the actyl analog XXIV is first converted to the dimethylaminoacryloyl analog XXV, which is then converted to the pyrazole XXVI byreaction with a hydrazide. A person of skill in the art will appreciatethat the pyrazole moiety can alternatively be formed prior to amideformation.

In another example, the pyrazole moiety can be coupled to the remainderof the molecule via a nitrogen atom, e.g., as outline in Scheme 7b.

In Scheme 7b, X¹, X³, R², R⁴ and R^(4a) are defined as herein above(see, e.g., Scheme 1a).

Pyridine/Pyrazine

In another example, the compounds of the present disclosure include a6-membered heteroaromatic ring, such as a pyridine or pyrazine moiety asthe ring Z. Such molecules can be prepared using a procedure outlined inSchemes 8a or 8b, below.

In Scheme 8a, Y⁵ is N or CR⁴. X¹, X³, R², R⁴, R^(4a), Cy, W and thecatalyst are defined as herein above (see, e.g., Scheme 1a and Scheme1b). In one example, the catalyst is a palladium phosphine, e.g.,Pd(PPh₃)₄.

Alternatively, the pyridine or pyrazine moiety can be coupled prior toamide formation starting from the nitro analog XIII as outline in Scheme8b, below.

In Scheme 8b, Y⁵ is N or CR⁴. X¹, X³, R², R⁴, R^(4a), Cy, W and thecatalyst are defined as herein above (see, e.g., Scheme 1a and Scheme1b). In one example, the catalyst is a palladium phosphine, e.g.,Pd(PPh₃)₄.

Synthesis of Substituted Thiophene Analogs

In one example, the compounds of the present disclosure include asubstituted thiophene ring. For example, in Formulae (II) to (XV), R²and/or R^(2a) is other than H. Halogen-substituted analogs may beprepared using the procedure outlined in Scheme 9.

In Scheme 9, R^(b) is a ring and X is a halogen (e.g., Br or Cl). In oneexample, X in Scheme 9 is Br. In another example, R^(b) is chosen fromsubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl. for example, R^(b) is 9H-fluorene. In Scheme9, the isothiocyanate XXVII is cyclized with the chloro beta-ketoesterXXVIII in the presence of a base to give the carbamate XXIX.Deprotection of the amino group (e.g., using morpholine to removefluorene protecting group) affords the halogenated thiophene ester XXXI.Compound XXI can be further converted to an amide by coupling to anappropriate carboxylic acid, similarly to the reaction outlined inScheme 1.

Alternatively the halogen can be replaced with another moiety (e.g.,either before deprotection of the amino group, or after coupling of theamine with an appropriate carboxylic acid to form an amide). In oneexample, the halogen X (e.g., Br) in Scheme 9), can be replaced with atrifluoro-methyl (—CF₃) group, e.g., using CF₃—CO₂—CuI or methyl2,2-difluoro-2-(fluorosulfonyl)acetate/CuI. In another example, halogenX is replaced with halogen X* or CN, e.g., utilizing Sandmeyer orSandmeyer-type reactions. For example, Br can be replaced with Cl, usinga reagent including CuCl (CuCl/DMF) or with CN using a reagent includingCuCN (e.g., CuCN/DMF). The substitution of one halogen for another canbe performed at different stages of the synthesis. For example, compoundXXXI in Scheme 9 can first be converted to an amide and the resultinganalog can be subjected to halogen exchange. Subsequently the estermoiety can be converted to an heteroaryl group (e.g., a triazolemoiety), e.g., using the methods described herein.

Analogs including an alkyl group as R² can be prepared using appropriatestarting materials such as methyl-2-amino-4-methyl-3-thiophenecarboxylate, which is commercially available (e.g., Oakwood,Fluorochem):

Pharmaceutical Compositions

The disclosure further provides pharmaceutical compositions including acompound of the present disclosure, e.g., those of Formulae (I) to (XV)(or any embodiment thereof), and at least one pharmaceuticallyacceptable carrier. The term “pharmaceutically acceptable carrier” meansall pharmaceutically acceptable ingredients known to those of skill inthe art, which are typically considered non-active ingredients. The term“pharmaceutically acceptable carrier” includes solvents, solid or liquiddiluents, vehicles, adjuvants, excipients, glidants, binders,granulating agents, dispersing agents, suspending agents, wettingagents, lubricating agents, disintegrants, solubilizers, stabilizers,emulsifiers, fillers, preservatives (e.g., anti-oxidants), flavoringagents, sweetening agents, thickening agents, buffering agents, coloringagents and the like, as well as any mixtures thereof. Exemplary carriers(i.e., excipients) are described in, e.g., Handbook of PharmaceuticalManufacturing Formulations, Volumes 1-6, Niazi, Sarfaraz K., Taylor &Francis Group 2005, which is incorporated herein by reference in itsentirety. A pharmaceutical composition of the present disclosure mayinclude one or more compounds of the present disclosure in associationwith one or more pharmaceutically acceptable carrier and optionallyother active ingredients.

The compounds of the present disclosure may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing at least one pharmaceutically acceptablecarrier. The term “parenteral” as used herein includes percutaneous,subcutaneous, intravascular (e.g., intravenous), intramuscular, orintrathecal injection or infusion techniques and the like. Thepharmaceutical compositions containing compounds of the presentdisclosure may be in a form suitable for oral use, for example, astablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsion, hard or soft capsules, or syrups orelixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agents chosenfrom the group consisting of sweetening agents, flavoring agents,coloring agents and preservative agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques. In some cases such coatings may be prepared by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatincapsules, wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example, peanut oil, liquid paraffin orolive oil. Formulations for oral use may also be presented as lozenges.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of a aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agents or suspending agents areexemplified by those already mentioned above. Additional excipients, forexample sweetening, flavoring and coloring agents, may also be present.

Pharmaceutical compositions of the present disclosure may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil ora mineral oil or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspensions. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono-or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of the present disclosure may also be administered in theform of suppositories, e.g., for rectal administration of the drug.These compositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols.

Compounds of the present disclosure may be administered parenterally ina sterile medium. The compound, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.In one embodiment, adjuvants such as local anesthetics, preservativesand buffering agents can be dissolved in the vehicle.

For disorders of the eye or other external tissues, e.g., mouth andskin, the formulations are applied, for example, as a topical gel,spray, ointment or cream, or as a scleral suppository, containing theactive ingredients in a total amount of, for example, 0.075 to 30% w/w,0.2 to 20% w/w or such as 0.4 to 15% w/w. When formulated in anointment, the active ingredients may be employed with either paraffinicor a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound, which enhances absorption or penetrationof the active ingredient through the skin or other affected areas.Examples of such dermal penetration enhancers include dimethylsulfoxideand related analogs. The compounds of this present disclosure can alsobe administered by a transdermal device. In one embodiment, topicaladministration will be accomplished using a patch either of thereservoir and porous membrane type or of a solid matrix variety. Ineither case, the active agent is delivered continuously from thereservoir or microcapsules through a membrane into the active agentpermeable adhesive, which is in contact with the skin or mucosa of therecipient. If the active agent is absorbed through the skin, acontrolled and predetermined flow of the active agent is administered tothe recipient. In the case of microcapsules, the encapsulating agent mayalso function as the membrane. The transdermal patch may include thecompound in a suitable solvent system with an adhesive system, such asan acrylic emulsion, and a polyester patch. The oily phase of theemulsions of this present disclosure may be constituted from knowningredients in a known manner. While the phase may comprise merely anemulsifier, it may comprise a mixture of at least one emulsifier with afat or oil or with both a fat and an oil. In one embodiment, ahydrophilic emulsifier is included together with a lipophilicemulsifier, which acts as a stabilizer. The phase may, for example,include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily, dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present disclosure include Tween 60, Span 80, cetostearylalcohol, myristyl alcohol, glyceryl monostearate, and sodium laurylsulfate, among others. The choice of suitable oils or fats for theformulation is based on achieving the desired cosmetic properties, sincethe solubility of the active compound in most oils likely to be used inpharmaceutical emulsion formulations is very low. Thus, the cream may,for example, be a non-greasy, non-staining and washable product withsuitable consistency to avoid leakage from tubes or other containers.Straight or branched chain, mono- or dibasic alkyl esters such asdi-isoadipate, isocetyl stearate, propylene glycol diester of coconutfatty acids isopropyl myristate, decyl oleate, isopropyl palmitate,butyl stearate, 2-ethylhexyl palmitate or a blend of branched chainesters may be used. These may be used alone or in combination dependingon the properties required. Alternatively, high melting point lipidssuch as white soft paraffin and/or liquid paraffin or other mineral oilscan be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The anti-inflammatory active ingredients may, for example,be present in such formulations in a concentration of 0.5 to 20%, suchas 0.5 to 10%, for example about 1.5% w/w. For therapeutic purposes, theactive compounds of the present disclosure are ordinarily combined withone or more adjuvants appropriate to the indicated route ofadministration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tableted or encapsulated for convenient administration. Suchcapsules or tablets may contain a controlled-release formulation as maybe provided in a dispersion of active compound in hydroxypropylmethylcellulose. Formulations for parenteral administration may be in the formof aqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solutions and suspensions may be prepared fromsterile powders or granules having one or more of the carriers ordiluents mentioned for use in the formulations for oral administration.The compounds may be dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvantsand modes of administration are well and widely known in thepharmaceutical art.

Dosage levels of the order of from about 0.005 mg to about 80 mg perkilogram of body weight per day are useful in the treatment of thediseases and conditions described herein (e.g., about 0.35 mg to about5.6 g per human patient per day, based on an average adult person weightof 70 kg). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient. The daily dose can be administered in one tofour doses per day. In the case of skin conditions, it may, for example,be applied as a topical preparation of compounds of this presentdisclosure on the affected area one to four times a day.

Formulations suitable for inhalation or insufflation include solutionsand suspensions in pharmaceutically acceptable aqueous or organicsolvents, or mixtures thereof, and powders. The liquid or solidcompositions may contain suitable pharmaceutically acceptable excipientsas describe above. The compositions may be administered by oral or nasalrespiratory route for local or systemic effect. Compositions may benebulized by use of inert gases or vaporized, and breathed directly fromthe nebulizing/vaporizing device or the nebulizing device may beattached to a facemask tent or intermittent positive pressure-breathingmachine.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It may be convenient toformulate the animal feed and drinking water compositions so that theanimal takes in a therapeutically appropriate quantity of thecomposition along with its diet. It may also be convenient to presentthe composition as a premix for addition to the feed or drinking water.

Methods

Over-activation of JNK is believed to be an important mechanism inautoimmune, inflammatory, metabolic, neurological diseases as well ascancer and pain. Certain compounds of the present disclosure exhibitinhibitory activity against JNK (e.g., JNK1, JNK2 and JNK3). Kinaseactivity can be determined using a kinase assay, which typically employsa kinase substrate and a phosphate group donor, such as ATP (or aderivative thereof). Exemplary kinase substrates for various kinases aredescribed in Example 14. The kinase catalyzes the transfer of aphosphate group from the phosphate group donor (e.g., ATP) unto thesubstrate forming a covalent bond. Certain compounds of the presentdisclosure can inhibit the activity of the kinase, slowing the abovedescribed reaction and resulting in a smaller number of phosphate groupsbeing transferred. Hence, the current disclosure provides a method(i.e., an in vitro assay) that includes: (i) contacting a compound ofthe present disclosure with a kinase (e.g., JNK, p38, MAPK and the like)thereby forming a mixture. The method may further include (ii)contacting the mixture with a kinase substrate (e.g., peptide substrate)and ATP (or a derivative thereof), thereby forming an amount ofphosphorylated kinase substrate. The method can further include (iii)measuring the amount of phosphorylated kinase substrate. The amount ofphosphorylated substrate may be accomplished using a detection reagent.Suitable detection reagents can include a metal reagent, such as alanthanoid (e.g., Eu-63), a radioactive probe, a labeled (e.g.,fluorescently labelled) antibody and combinations thereof. In oneexample, the assay is a fluorescence resonance energy transfer (FRET)assay (e.g., TR-FRET). Examples of such assays are described in Example14. In another embodiment, compounds of the present disclosure is usedas a reference standard to determine the in vitro activity of othercompounds in a kinase assay as described above. In another example, thecompounds of the present disclosure is used in an in vitro assay foridentifying candidate compounds that are capable of inhibiting JNK.

Over-activation of JNK is believed to be an important mechanism inautoimmune, inflammatory, metabolic, neurological diseases as well ascancer and pain. Hence, compounds and compositions of the presentdisclosure may be useful in the treatment and/or prevention of c-JunN-terminal kinase mediated disorders, such as autoimmune disorders,inflammatory disorders, metabolic disorders, neurological diseases, painand cancer.

One member of the JNK family, Jnk3, may be required for stress-inducedneuronal apoptosis, as it is selectively expressed in the nervoussystem. Thus, the compounds of the present disclosure may be useful forthe treatment of neurodegenerative diseases, such as Alzheimer'sdisease, Parkinson's disease and other diseases and conditionscharacterized by neuronal cell death, such as stroke. An in vivo model,which can be used to assess the potential in vivo beneficial effect ofthe compounds of the present disclosure, is described in Example 15.

Excitotoxic cell death can be induced experimentally by theadministration of kainic acid, a potent agonist of the kainate class ofglutamate receptors. Peripheral injection of kainic acid results inrecurrent seizures and degeneration of select populations of neurons inthe hippocampus. Activation of jnk is observed after kainic acidtreatment in vivo (see, e.g., Jeon S. H. et al, Experimental andMolecular Medicine 2000, 32(4): 227-230 and Kim Y.-H. et al., Moleculesand Cells 2001, 11(2): 144-150). Mice lacking the Jnk3 gene areresistant to kainic acid-induced upregulation of phosphorylated c-jun(p-cjun) and hippocampal neuronal apoptosis (see e.g., Yang D. D. etal., Nature 1997, 389: 865-870). Phosphorylated c-jun in wildtype miceis upregulated after kainic acid administration and demonstrate thatthis upregulation is inhibited by compounds of the present disclosure.

The disclosure provides a method for reducing the upregulation ofphosphorylated c-jun (e.g., which is induced by an excitatory amino acidor an analog thereof), in the brain of a test animal, such as a rodent(e.g., mice, rat, rabbit and the like). The method includesadministering to the test animal a compound or composition of thepresent disclosure. The method can further include administering to thetest animal an excitatory amino acid, such as kainic acid. The methodcan further include measuring the amount of phosphorylated c-jun in thebrain (e.g., hippocampus) of the test animal.

In one example, the disclosure provides a method of treating a disease.The method includes administering to a mammalian subject (e.g., human)in need thereof a therapeutically effective amount of a compound or saltof the present disclosure, for example those according to any one ofFormulae I to XV (or any embodiment thereof), or a compositioncomprising such compounds or salts.

In one example, the disease is a neurodegenerative disease. In anotherexample, the disease is an infectious disease (e.g., sepsis, septicshock and Shigellosis). In yet another example, the disease is anautoimmune disease. In a further example, the disease is a destructivebone disorder, such as osteoporosis, osteoarthritis and multiplemyeloma-related bone disorders.

Neurodegenerative diseases which may be treated by the compounds of thisdisclosure include, but are not limited to Alzheimer's disease (AD),diffuse Lewy body type of Alzheimer's disease, Parkinson's disease, Downsyndrome, dementia, mild cognitive impairment (MCI), amyotrophic lateralsclerosis (ALS), traumatic brain injuries, cerebral ischemic braindamage, ischemic or hemorrhaging stroke, multi-infarct dementia,hereditary cerebral hemorrhage with amyloidosis of the dutch-type,cerebral amyloid angiopathy (including single and recurrent lobarhemorrhages), neurodegeneration induced by viral infection (e.g. AIDS,encephalopathies) and other degenerative dementias, including dementiasof mixed vascular and degenerative origin, dementia associated withParkinson's disease, dementia associated with progressive supranuclearpalsy, dementia associated with cortical basal degeneration.Neurodegenerative diseases also includes epilepsy, seizures,neurodegenerative disease caused by traumatic injury,ischemia/reperfusion in stroke, cerebral ischemias, acute hypoxia andischemia or glutamate neurotoxicity. In a one example, theneurodegenerative disease is Alzheimer's disease or diffuse Lewy bodytype of Alzheimer's disease. In one example, the neurodegenerativedisease which can be treated using the compounds of this disclosure isAlzheimer's disease. The treatment of Alzheimer's disease (AD) caninclude methods of treating a patient who has AD, methods of preventinga patient from getting AD, methods of preventing or delaying the onsetof AD; e.g., delaying or preventing the progression MCI to AD. Inanother example, the neurodegenerative disease is diffuse Lewy body typeof Alzheimer's disease. In yet another example, the disease is mildcognitive impairment (MCI).

In another embodiment, the disclosure provides a method of treating adisease chosen from epilepsy, seizures, Huntington's disease, multiplesclerosis, cancer, age-related macular degeneration, diabeticretinopathy and retinal neurodegeneration related to glaucoma or oculartrauma, the method comprising administering to a mammalian subject(e.g., a human subject) in need thereof a pharmaceutically effectiveamount of a compound or salt of any one of Formulae I to XV (or anembodiment thereof) or a pharmaceutical composition comprising at leastone compound of Formulae I to XV (or an embodiment thereof). Otherdiseases, which may be treated using the compounds of the presentdisclosure include alcoholism, Alexander's disease, Alper's disease,ataxia telangiectasia, Batten disease (also known asSpielmeyer-Vogt-Sjogren-Batten disease), prior disease, bovinespongiform encephalopathy (BSE), Canavan disease, cerebral palsy,Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease,frontotemporal lobar degeneration, Huntington's disease, HIV-associateddementia, Kennedy's disease, Krabbe's disease, Lewy body dementia,neuroborreliosis, Machado-Joseph disease (e.g., spinocerebellar ataxiatype 3), multiple system atrophy, multiple sclerosis, narcolepsy,Niemann Pick disease, Pelizaeus-Merzbacher disease, Pick's disease,primary lateral sclerosis, progressive supranuclear palsy, Refsum'sdisease, Sandhoff's disease, Schilder's disease, subacute combineddegeneration of spinal cord secondary to pernicious anaemia,spinocerebellar ataxia (multiple types with varying characteristics),spinal muscular atrophy, Steele-Richardson-Olszewski disease and tabesdorsalis.

Automimmune diseases which may be treated or prevented by the compoundsof this present disclosure include, but are not limited to,glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus,seleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis and graft versus hostdisease (GVHD). The compounds and compositions of the present disclosuremay also be useful to treat pathologic immune responses such as thatcaused by T cell activation and thrombin-induced platelet aggregation.

Additional specific conditions or diseases that may be treated with thecompounds or compositions of the present disclosure include, withoutlimitation, myocardial ischemia, ischemia/reperfusion in heart attacks,organ hypoxia, vascular hyperplasia, cardia and renal reperfusioninjury, thrombosis, cardiac hypertrophy, hepatic ischemia, liverdisease, congestive heart failure, thrombin induced plateletaggregation, endotoxemia and/or toxic shock syndrome, and conditionsassociated with prostaglandin endoperoxidase synthase-2.

In other embodiments, the specific conditions or diseases that may betreated with the compounds or compositions of the present disclosureinclude, without limitation, angiogenic disorders, including solidtumors, liquid tumors, tumor metastasis, ocular neovasculization,infantile haemangiomas. Proliferative diseases which may be treated orprevented by the compounds of this disclosure include, but are notlimited to, acute myelogenous leukemia, chronic myelogenous leukemia,metastatic melanoma, Kaposi's sarcoma, multiple myleoma and HTLV-1mediated tumorigenesis.

Other specific conditions or diseases that may be treated with thecompounds or compositions of the present disclosure include, withoutlimitation, acute pancreatitis, chronic pancreatitis, asthma, allergies,adult respiratory distress syndrome, chronic obstructive pulmonarydisease, glomerulonephritis, rheumatoid arthritis, systemic lupuserythematosis, scleroderma, chronic thyroiditis, Grave's disease,diabetes, thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis, graft versus hostdisease (GVHD), inflammatory reaction induced by endotoxin,tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriaticarthritis, Reiter's syndrome, gout, traumatic arthritis, rubellaarthritis, acute synovitis, pancreatic beta-cell disease; diseasescharacterized by massive neutrophil infiltration, rheumatoidspondylitis, gouty arthritis and other arthritic conditions, cerebralmalaria, chronic pulmonary inflammatory disease, silicosis, pulmonarysarcoisosis, bone resorption disease, allograft rejections, fever andmyalgias due to infection, cachexia secondary to infection, meloidformation, scar tissue formation, ulcerative colitis, pyresis,influenza, osteoporosis, osteoarthritis and multiple myeloma-relatedbone disorder.

In addition, JNK inhibitors of the instant disclosure may be capable ofinhibiting the expression of inducible pro-inflammatory proteins.Therefore, other “JNK-mediated conditions” which may be treated by thecompounds of this disclosure include edema, analgesia, fever and pain,such as neuromuscular pain, migrains, cancer pain, dental pain andarthritis pain.

In addition to the compounds of this disclosure, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this disclosuremay also be employed in compositions to treat or prevent theabove-identified disorders.

The disclosures in this document of all articles and references,including patents, are incorporated herein by reference in theirentirety.

The instant disclosure is illustrated further by the following examples,which are not to be construed as limiting the present disclosure inscope or spirit to the specific procedures described in them. Analogousstructures and alternative synthetic routes within the scope of thepresent disclosure will be apparent to those skilled in the art.

EXAMPLES General:

Reagents and solvents obtained from commercial suppliers were usedwithout further purification unless otherwise stated. Thin layerchromatography was performed on precoated 0.25 mm silica gel plates (E.Merck, silica gel 60, F₂₅₄). Visualization was achieved using UVillumination or staining with phosphomolybdic acid, ninhydrin or othercommon staining reagents. Flash chromatography was performed usingeither a Biotage Flash 40 system and prepacked silica gel columns orhand packed columns (E. Merck silica gel 60, 230-400 mesh). PreparatoryHPLC was performed on a Varian Prepstar high performance liquidchromatograph. ¹H and ¹³C NMR spectra were recorded at 300 MHZ and 75MHz, respectively, on a Varian Gemini or Bruker Avance spectrometer.Chemical shifts are reported in parts per million (ppm) downfieldrelative to tetramethylsilane (TMS) or to proton resonances resultingfrom incomplete deuteration of the NMR solvent (δscale). Mass spectrawere recorded on an Agilent series 1100 mass spectrometer connected toan Agilent series 1100 HPLC.

Compound purity was typically determined by HPLC/MS analysis using avariety of analytical methods. Exemplary methods are described below.

-   [1]=20% [B]:80% [A] to 70% [B]:30% [A] gradient in 1.75 min, then    hold, at 2 mL/min, where [A]=0.1% trifluoroacetic acid in water;    [B]=0.1% trifluoroacetic acid in acetonitrile on a Phenomenex Luna    C18 (2) 4.6 mm×30 cm column, 3 micron packing, 210 nm detection, at    35° C.-   [2]=50% [B]:50% [A] to 95% [B]:5% [A] gradient in 2.5 min, then    hold, at 2 mL/min, where [A]=0.1% trifluoroacetic acid in water;    [B]=0.1% trifluoroacetic acid in acetonitrile on a Phenomenex Luna    C18 (2) 4.6 mm×30 cm column, 3 micron packing, 210 nm detection, at    35° C.-   [3]=5% [B]:95% [A] to 20% [B]:80% [A] gradient in 2.5 min, then    hold, at 2 mL/min, where [A]=0.1% trifluoroacetic acid in water;    [B]=0.1% trifluoroacetic acid in acetonitrile on a Phenomenex Luna    C18 (2) 4.6 mm×30 cm column, 3 micron packing, 210 nm detection, at    35° C.-   [4]=20% [B]:80% [A] to 70% [B]:30% [A] gradient in 2.33 min, then    hold, at 1.5 mL/min, where [A]=0.1% trifluoroacetic acid in water;    [B]=0.1% trifluoroacetic acid in acetonitrile on a Phenomenex Luna    C18 (2) 4.6 mm×30 cm column, 3 micron packing, 210 nm detection, at    35° C.-   [5]=50% [B]:50% [A] to 95% [B]:5% [A] gradient in 3.33 min, then    hold, at 1.5 mL/min, where [A]=0.1% trifluoroacetic acid in water;    [B]=0.1% trifluoroacetic acid in acetonitrile on a Phenomenex Luna    C18 (2) 4.6 mm×30 cm column, 3 micron packing, 210 nm detection, at    35° C.-   [6]=5% [B]:95% [A] to 20% [B]:80% [A] gradient in 3.33 min, then    hold, at 1.5 mL/min, where [A]=0.1% trifluoroacetic acid in water;    [B]=0.1% trifluoroacetic acid in acetonitrile on a Phenomenex Luna    C18 (2) 4.6 mm×30 cm column, 3 micron packing, 210 nm detection, at    35° C.-   [7]=20% [B]:80% [A] to 70% [B]:30% [A] gradient in 10.0 min, then    hold, at 1.5 mL/min, where [A]=0.1% trifluoroacetic acid in water;    [B]=0.1% trifluoroacetic acid in acetonitrile on a Phenomenex Luna    C18 (2) 4.6 mm×3 cm column, 3 micron packing, 210 nm detection, at    35° C.-   [8]=10% [B]:90% [A] to 40% [B]:60% [A] gradient in 10.0 min, then    hold, at 1.5 mL/min, where [A]=0.1% trifluoroacetic acid in water;    [B]=0.1% trifluoroacetic acid in acetonitrile on a Phenomenex Luna    C18 (2) 4.6 mm×3 cm column, 3 micron packing, 210 nm detection, at    35° C.-   [9]=23% [B]:77% [A] to 30% [B]:70% [A] gradient in 15.0 min, then    hold, at 1.0 mL/min, where [A]=0.1% trifluoroacetic acid in water;    [B]=0.1% trifluoroacetic acid in acetonitrile on a Zorbex SB-phenyl    C18 2.1 mm×5 cm column, 5 micron packing, 210 nm detection, at 30°    C.-   [10]=50% [B]:50% [A] to 95% [B]:5% [A] gradient in 10.0 min, then    hold, at 1.5 mL/min, where [A]=0.1% trifluoroacetic acid in water;    [B]=0.1% trifluoroacetic acid in acetonitrile on a Phenomenex Luna    C18 (2) 4.6 mm×3 cm column, 3 micron packing, 210 nm detection, at    35° C.-   [11]=5% [B]:95% [A] to 20% [B]:80% [A] gradient in 10.0 min, then    hold, at 1.5 mL/min, where [A]=0.1% trifluoroacetic acid in water;    [B]=0.1% trifluoroacetic acid in acetonitrile on a Phenomenex Luna    C18 (2) 4.6 mm×3 cm column, 3 micron packing, 210 nm detection, at    35° C.-   [12]=30% [B]:70% [A] to 60% [B]:40% [A] gradient in 30 min, then    hold, at 16 mL/min, where [A]=0.1% trifluoroacetic acid in water;    [B]=0.1% trifluoroacetic acid in acetonitrile on a Phenomenex    synergi Hydro-RP 2×25 cm column, 4.0 micron pacing, 210 nm    detection, at 35° C.-   [13]=10% [B]:90% [A] to 40% [B]:60% [A] gradient in 10.0 min, then    hold, at 1.5 mL/min, where [A]=0.1% trifluoroacetic acid in water;    [B]=0.1% trifluoroacetic acid in acetonitrile on a Phenomenex    Synergi Polar-RP 4.6 mm×5 cm column, 2.5 micron packing, 210 nm    detection, at 35° C.

General Procedures: Protocol A

To a solution of the carboxylic acid (e.g., 1.00 mmol) and the amine(e.g., 1.00 mmol) in pyridine (e.g., 0.5 M) at about 0° C. was addedphosphorus oxychloride (POCl₃, e.g., 1.1 mmol) and the resultingsolution was stirred at about 0° C. for about 30 minutes. Water wasadded to the reaction mixture and the resulting solution was diluted(e.g., with methylene chloride). The mixture was washed with saturatedaqueous NaHCO₃ and the aqueous phase was separated and extracted withmethylene chloride. The combined organic phases were dried (e.g.,Na₂SO₄), filtered, concentrated under vacuum and the residue wasoptionally purified (e.g., silica gel column chromatography and/orpreparative HPLC).

Protocol B

To a solution of the carboxylic acid (e.g., 1.00 mmol) and the amine(e.g., 1.00 mmol) in methylene chloride (e.g., 0.3 M) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl, e.g.,1.20 mmol) and 1-hydroxybenzotriazole (HOBt, e.g. 0.10 mmol). Thereaction mixture was stirred at room temperature for about 18 h and wassubsequently washed with 1 N aqueous HCl and saturated NaHCO₃. Theorganic phase was separated, dried (Na₂SO₄), filtered, concentratedunder vacuum and the residue was optionally purified (e.g., silica gelcolumn chromatography).

Protocol C

The carboxamide (e.g., 1.00 mmol) was dissolved in dimethylformamidedimethylacetal (DMF-DMA, e.g., 10.0 mmol) and the resulting solution washeated to about 110° C. for about 30 minutes. The solution wasconcentrated under vacuum and the residue was dissolved in acetic acid(e.g., 0.5 M). Hydrazine monohydrate (e.g., 1.10 mmol) was added to thesolution and the mixture was heated to about 90° C. for about 30minutes. The reaction mixture was concentrated under vacuum and theresidue was optionally purified (e.g., by preparative HPLC).

Protocol D

The carboxamide (e.g., 1.00 mmol) was dissolved in dimethylacetamidedimethylacetal (DMA-DMA, e.g., 10.0 mmol) and the resulting solution washeated to about 110° C. for about 30 minutes. The solution wasconcentrated under vacuum and the residue was dissolved in acetic acid(e.g., 0.5 M). Hydrazine monohydrate (e.g., 1.10 mmol) was added to thesolution and the mixture was heated to about 90° C. for about 30minutes. The reaction mixture was concentrated under vacuum and theresidue was purified by preparative HPLC.

Protocol E

The chlorothiophene (e.g., 1.00 mmol), stannane (e.g., 1.00 mmol), andPd(PPh₃)₄ (e.g., 0.1 mmol) were dissolved in DMF (e.g., 0.5 M) and thereaction vessel was evacuated and purged with nitrogen three times. Thereaction mixture was heated to about 95° C. for about 18 h and theresulting solution was cooled to room temperature and diluted with Et₂O.The solution was washed with brine and the organic phase was separated,dried (Na₂SO₄), filtered, concentrated under vacuum and optionallypurified (e.g., silica gel column chromatography).

Protocol F

The nitrothiophene and 10% palladium on carbon in ethyl acetate (e.g., 3mL) was shaken under a hydrogen atmosphere (e.g., 40 psi) for about 2 h.The resulting suspension was filtered through a pad of diatomaceousearth and the filtrate was concentrated under vacuum.

Protocol G

CuCl (e.g., 5 mmol) was added to a solution of the bromothiophene (e.g.,1 mmol) in DMF (e.g., 0.3 M) and the resulting suspension was placedinto a heated oil bath (e.g., 140° C.). The mixture was stirred forabout 15 minutes and then removed from the oil bath. The resultingsolution was diluted with Et₂O and washed with brine. The organic phasewas separated, dried (Na₂SO₄), filtered, concentrated under vacuum andoptionally purified (e.g., silica gel column chromatography).

Protocol H

Ammonium chloride (e.g., 0.05 mmol) was added to a solution of themethyl ester (e.g., 1 mmol) in concentrated aqueous ammonium hydroxide(e.g., 0.3 M) in a glass pressure tube. The tube was sealed and thereaction mixture was placed in a heated oil bath (e.g., 90° C.). Afterstirring for about 2 h the reaction was cooled to room temperature anddiluted with water. The resulting solution was extracted with ethylacetate and the organic phases were combined, dried (Na₂SO₄), filtered,concentrated under vacuum and optionally purified (e.g., silica gelcolumn chromatography).

Protocol I

DMF-DMA (e.g., 1.00 mmol) was added to a solution of the carboxamide(e.g., 1.00 mmol) in methylene chloride (e.g., 0.2 M) and the resultingsolution was stirred at room temperature for about 30 minutes. Thesolution was concentrated under vacuum and the residue was dissolved inacetic acid (e.g., 0.5 M). Hydrazine monohydrate (e.g., 1.10 mmol) wasadded to the solution and the mixture was stirred at room temperaturefor about 5 minutes. The reaction mixture was concentrated under vacuumand the residue was optionally purified (e.g., preparative HPLC).

Protocol J

DMF-DMA (e.g., 2.00 mmol) was added to a solution of the carboxamide(e.g., 1.00 mmol) in methylene chloride (e.g., 0.2 M) and the resultingsolution was stirred at room temperature for about 30 minutes. Thesolution was concentrated under vacuum and the residue was dissolved inacetic acid (e.g., 0.5 M). Methylhydrazine (e.g., 2.0 mmol) was added tothe solution and the mixture was stirred at room temperature for about 5minutes. The reaction mixture was concentrated under vacuum and theresidue was optionally purified (e.g., preparative HPLC).

Protocol K

Sodium hydride (e.g., 2 mmol) was added to a solution of the lactam(e.g., 1 mmol) in DMF (e.g., 0.2 M) at about 0° C. The resultingsuspension was stirred for about 15 minutes after which methyl2-bromoacetate (e.g., 1.2 mmol) was added. The reaction mixture wasstirred at room temperature for about 1 h and was then diluted (e.g.,with Et₂O). The solution was washed with brine and the organic phase wasseparated, dried (e.g., Na₂SO₄), filtered, concentrated under vacuum andpurified (e.g., silica gel column).

Protocol L

To a solution of the carboxylic acid (e.g., 1.00 mmol) and the amine(e.g., 1.00 mmol) in DMF (e.g., 0.3 M) was added EDCl (e.g., 3.5 mmol),DMAP (e.g., 0.5 mmol) and HOBt (e.g., 0.5 mmol). The reaction mixturewas stirred at room temperature for about 8 h and was subsequentlydiluted (e.g., with ethyl acetate) and washed with brine. The organicphase was separated, dried (e.g., Na₂SO₄), filtered, concentrated undervacuum and the residue was purified (e.g., silica gel column and/orpreparative HPLC).

Protocol M

The aryl halide (e.g., 1.00 mmol), triethylamine (e.g., 2.00 mmol) andP(o-tol)₃ (e.g., 0.30 mmol) were dissolved in acetonitrile (e.g., 0.5 M)in a glass pressure tube and nitrogen gas was bubbled through thesolution via a gas dispersion tube for 10 minutes. Ethyl acrylate (e.g.,1.25 mmol) and palladium acetate (e.g., 0.10 mmol) were added to thereaction mixture and the tube was sealed and placed into an oil bathpreheated to about 120° C. for about 18 h. The resulting solution wasconcentrated under vacuum and purified (e.g., silica gel column).

Protocol N

Sodium ethoxide (e.g., 4 mmol of a 21% solution in ethanol) was added toa solution of the acrylate (e.g., 1.00 mmol) in ethanol (e.g., 0.5 M)and the resulting solution was heated to about 60° C. for about 2 h. Thereaction mixture was diluted (e.g., with ethyl acetate) and washed withbrine. The organic phase was separated, dried (e.g., Na₂SO₄), filtered,concentrated under vacuum and the residue was purified (e.g., silica gelcolumn).

Synthesis of Various Intermediates 2-(6-Fluoroquinolin-5-yl)acetic acidand 2-(6-fluoroquinolin-7-yl)acetic acid Protocol O

to a solution of o-fluoro benzoic acid (30.0 g, 0.19 mol) in conc.sulfuric acid (50 mL) and water (10 mL) was added dropwise a solution offuming nitric acid (10 mL) in water (10 mL) at 0° C. The reactionmixture was stirred at 0° C. for 30 min. The resulting precipitate wasfiltered off and washed with cold water, dried in vacuum to give2-(2-fluoro-5-nitrophenyl)acetic acid as a white solid (35.2 g, 91%).

To a suspension of 2-(2-fluoro-5-nitrophenyl)acetic acid (15.0 g, 75.3mmol) in ethanol (800 mL), THF (400 mL), and water (200 mL) was addedammonium chloride (4.46 g, 83.4 mmol) and ferrous powder (25.04 g, 405.4mmol). The resulting mixture was heated at 80° C. for 1 hr and theprogress of the reaction was monitored by TLC. Upon complete consumptionof starting material, the reaction mixture was filtered off while it washot. The filtrate was evaporated under vacuum and the crude residue wasdiluted with ethyl acetate (200 mL) and washed with water (3×100 mL).The combined organic layer was washed with brine, dried over Na₂SO₄ andevaporated under vacuum to afford 2-(5-amino-2-fluorophenyl)acetic acidas a grey solid which was used for the next step without furtherpurification (6.13 g, 48%).

To a solution of 2-(5-amino-2-fluorophenyl)acetic acid (6.13 g, 36.2mmol) in ethanol (15 mL) was added conc. sulfuric acid (2 mL) dropwise.The reaction mixture was stirred under N₂ at 80° C. for 1 hr. After thereaction mixture was cooled to RT and neutralized with aqueous Na₂CO₃ topH 7-8, the aqueous solution was extracted with ethyl acetate (3×100mL). The combined organic layer was washed with brine, dried over Na₂SO₄and evaporated under vacuum to afford ethyl2-(5-amino-2-fluorophenyl)acetate as a yellow oil which was used for thenext step without further purification (6.13 g, 95%).

To a mixture of ethyl 2-(5-amino-2-fluorophenyl)acetate (3.7 g, 18.8mmol), glycerol (6.92 g, 75.2 mmol), nitrobenzene (4.63 g, 37.6 mmol)and ferrous sulfate (1.06 g, 3.76 mmol) was added conc. sulfuric acid(4.5 mL) dropwise. The reaction mixture was heated at 120° C. for 15 hr.After cooled to RT, the reaction mixture was diluted with ethanol (20mL), and 2N aq. NaOH was introduced to adjust pH about 13. The resultingmixture was stirred at RT for 1 hr. Then the reaction was neutralizedwith aq. HCl and filtered, and the dark brown precipitate was washedwith methanol. The combined filtrate was concentrated to dryness invacuum. The resulting residue was washed adequately with methanol andthe combined filtrate was concentrated to dryness to give crude product,which was isolated by flash column chromatography to give2-(6-fluoroquinolin-5-yl)acetic acid and 2-(6-fluoroquinolin-7-yl)aceticacid (1.7 g, 44%). LC-MS (0.05% TFA): [M+1]⁺206.1. ¹H-NMR (DMSO-d6, 400MHz): δ 12.66 (brs, 1H), 8.90 (m, 1H), 8.35 (m, 1H), 8.04 (m, 1H), 7.76(m, 1H), 7.56 (m, 1H), 3.88 (s, 2H).

2-(8-Fluoroquinolin-5-yl)acetic acid

The title compound (1.2 g) was prepared from p-fluorobenzoic acid (10.1g, 65.5 mmol) according to Protocol O, above. LCMS (0.05% TFA):[M+1]⁺206.0. ¹H-NMR (CD₃OD, 400 MHz): δ 8.91 (d, 1H, J=2.8 Hz), 8.58 (d,1H, J=6.8 Hz), 7.68 (m, 1H), 7.53 (m, 1H), 7.50 (m, 1H), 4.12 (s, 2H).

2-(8-Trifluoromethyl)quinolin-5-yl)acetic acid

To a solution of 1,4-dibromo-2-nitrobenzene (5 g, 17.78 mmol) inN-methylpyrrolidinone (40 mL) were added methyldifluoro(fluorosulfonyl)acetate (4.5 mL, 35.6 mmol) and copper(I)iodide. The mixture was heated at 80° C. overnight, decolorized withactivated charcoal, diluted with brine and extracted with ethyl acetate(3×30 mL). The combined extracts was dried over MgSO₄, concentrated invacuum and purified by flash chromatography (0-100 percent ethyl acetatein petroleum) to give 4-bromo-2-nitro-1-(trifluoromethyl)benzene (4.1 g,85%) as a yellow oil.

To a suspension of 4-bromo-2-nitro-1-(trifluoromethyl)benzene (4.0 g,14.9 mmol) in ethanol (230 mL), THF (85 mL), and water (40 mL) was addedammonium chloride (1.0 g, 18.8 mmol) and ferrous powder (5.06 g, 90mmol). The resulting mixture was heated at 80° C. for 1 hr and theprogress of the reaction was monitored by TLC. Upon complete consumptionof staring material, the reaction mixture was filtered off while it washot. The filtrate was evaporated under vacuum and the crude residue wasdiluted with ethyl acetate (100 mL) and washed with water (3×50 mL). Thecombined organic layer was washed with brine, dried over Na₂SO₄ andevaporated under vacuum to afford 5-bromo-2-(trifluoromethyl)aniline asa solid (3.2 g, 90%).

To a mixture of 5-bromo-2-(trifluoromethyl)aniline (3.0 g, 12.6 mmol),glycerol (4.64 g, 50.0 mmol), and ferrous sulfate (0.56 g, 2.0 mmol) wasadded conc. sulfuric acid (2.2 mL) dropwise. The reaction mixture washeated at 120° C. for 4 hr. After cooled to RT, the reaction was dilutedwith ethyl acetate (150 mL), and 2N aq. NaOH was introduced to adjust pHabout 13. The organic layer was separated and washed with brine anddried over Na₂SO₄ and evaporated to give the crude product, which waspurified with flash column chromatography to give5-bromo-8-(trifluoromethyl)quinoline (1.2 g, 48%).

5-Bromo-8-(trifluoromethyl)quinoline (1.0 g, 3.6 mmol) was subjected toprotocol P to give tert-butyl2-(8-(trifluoromethyl)quinolin-5-yl)acetate (450 mg, 40%).

To a solution of tert-butyl 2-(8-(trifluoromethyl)quinolin-5-yl)acetate(400 mg, 1.28 mmol) in DCM (5 mL) was added TFA (10 mL) dropwise. Thereaction was stirred at room temperature overnight. After the reactionwas complete, the solvent was removed and the residue was purified(silica gel chromatography) to give the final product2-(8-(trifluoromethyl)quinolin-5-yl)acetic acid (180 mg, 54%). LC-MS(0.05% TFA): [M+1]⁺256.1. ¹H-NMR (DMSO-d6, 400 MHz): δ 12.70 (s, 1H),9.07 (m, 1H), 8.56 (m, 1H), 8.15 (d, 1H), 7.74 (m, 1H), 7.68 (m, 1H),4.23 (s, 2H). ¹³C-NMR (DMSO-d6, 100 MHz): δ 171.9, 151.0, 144.0, 138.3,133.5, 127.867, 127.83, 127.78, 125.3, 123.1, 122.2, 37.7.

2-(Isoquinolin-4-yl)acetic acid

5.2 g of Zn powder was put into a 250 mL of three-neck flask under N₂protection, and then 0.5 mL of TMSCl being dissolved in 20 mL of dry THFwas injected into the flask. The suspension mixture was stirred at roomtemperature for 20 minutes, and then 6 mL of tert-butyl 2-bromoacetatein 50 mL of dry THF was dropped into the flask for about 30 minutes at25-40° C. After the addition was complete, the reaction mixture wasstirred at 40° C. for another 30 minutes.

4-Bromoisoquinoline (2.0 g, 9.7 mmol) was subjected to protocol P togive a residue which as purified with silica gel chromatography to givetert-butyl 2-(isoquinolin-4-yl)acetate (1.9 g, 81%).

To a solution of tert-butyl 2-(isoquinolin-4-yl)acetate (1.8 g, 7.4mmol) in DCM (10 mL) was added TFA (10 mL) dropwise. The reaction wasstirred at room temperature overnight. After the reaction completed, thesolvent was evaporated and the residue was neutralized with aqueousammonia to pH 3-4, then the precipitate was filtered, washed with waterand ether, and the ether extract was collected to give the titlecompound (1.3 g, 93%) LC-MS (0.05% TFA): [M+1]⁻188.1. ¹H-NMR (DMSO-d6,400 MHz): δ 9.39 (s, 1H), 8.48 (s, 1H), 8.24 (d, 1H, J=6.4 Hz), 7.93 (t,1H), 7.79 (m, 1H), 4.11 (s, 2H).

2-(Isoquinolin-8-yl)acetic acid

2-bromobenzaldehyde (18.4 g, 0.1 mol) and 2,2-dimethoxyethanamine (11.55g, 0.11 mol) in 200 mL of toluene was heated to reflux for 4 hr. Thereaction mixture was evaporated under vacuum to give an oil of2-bromo-N-(2,2-dimethoxyethylidene)aniline which was used for the nextstep without purification. The oil was dropped into 50 mL ofconcentrated H₂SO₄ and the mixture was heated to 130-140° C. for 30mins, then the reaction mixture was poured into 500 mL if ice-water andadjust to pH˜8 with 5N sodium hydroxide solution. The aqueous solutionwas extracted with DCM (250 mL×5) and washed with water (3×50 mL). Thecombined organic layer was washed with brine, dried over Na₂SO₄ and thesolvent was evaporated under vacuum. The crude solid was purified withsilica gel to give 8-bromoisoquinoline (2.2 g, two steps 10.6%).

Protocol P

To a suspension of 8-bromoisoquinoline (2.0 g, 9.7 mmol), Q-phos (68 mg,0.096 mmol) and Pd(dba)₂ (132 mg, 0.14 mmol) in dry THF (30 mL) wasadded 40 mL of (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution underN₂ protection. The resulting mixture was heated at 80° C. overnight. Thesolvent was evaporated under vacuum and the crude residue was dilutedwith ethyl acetate (100 mL) and washed with water (3×50 mL). Thecombined organic layer was washed with brine, dried over Na₂SO₄ and thesolvent was evaporated under vacuum to give a residue which was purifiedwith silica gel chromatography to give tert-butyl2-(isoquinolin-8-yl)acetate (1.85 g, 78%).

to a solution of tert-butyl 2-(isoquinolin-8-yl)acetate (1.8 g) in DCM(10 mL) was added TFA (10 mL) dropwise. The reaction was stirred at roomtemperature overnight. After the reaction was complete, the solvent wasremoved to give a residue which as adjusted to pH 3-4 with aqueousammonia. The precipitate was filtered off and washed with water. Thefinal product was purified (silica gel column chromatography) to afford2-(isoquinolin-8-yl)acetic acid as a solid (1.2 g, 87%). LC-MS (0.05%TFA): [M+1]⁺188.1. ¹H-NMR (DMSO-d6, 400 MHz): δ 13.0 (brs, 1H), 9.65 (s,1H), 8.61 (d, 1H, J=4.8 Hz), 8.16 (d, 1H, J=4.8 Hz), 7.95 (d, 1H, J=6.8Hz), 7.92 (t, 1H), 7.72 (d, 1H, J=6.8 Hz), 4.29 (s, 2H).

2-(Quinolin-8-yl)acetic acid

The title compound (278 mg) was prepared from 8-bromoquinoline (3.0 g,14.5 mmol) according to protocol P above. LCMS (0.05% TFA): [M+1]⁺188.1.¹H-NMR (CD₃OD, 400 MHz): δ 9.01 (d, 1H, J=3.6 Hz), 8.72 (d, 1H, J=6.4Hz), 8.06 (d, 1H, J=6.8 Hz), 7.87 (d, 1H, J=5.6 Hz), 7.77 (m, 2H), 4.31(s, 2H).

Preparation of 2-(benzo[d]thiazol-7-yl)acetic acid

To a solution of 6-nitrobenzothiazole (3.8 g, 0.02 mol) in 40 ml 2N HClwas added SnCl₂ (15.9 g, 0.06 mol), and the mixture was stirred at roomtemperature overnight. The reaction mixture was treated withconcentrated NH₄OH to pH 11 and extracted with ethyl acetate (3×150 ml).The combined organic phase was concentrated under reduced pressure. Theresidue was purified (silica gel chromatography) to givebenzo[d]thiazol-6-amine (3 g, 72%).

To a solution of benzo[d]thiazol-6-amine (100 mg, 0.67 mmol) in 6 mlCHCl₃ was added Br₂ (42 mg, 0.27 mmol) in CHCl₃ (10 ml) dropwise about15 min. the mixture was concentrated under reduced pressure, and theresidue was crystallized from DCM:MeOH (5:1) to give7-bromobenzo[d]thiazol-6-amine (80 mg, 80%).

To a solution of bromobenzo[d]thiazol-6-amine (30 mg, 0.13 mmol) wasadded 50% H₂SO₄ (39 mg, 0.39 mmol), and then NaNO₂ (18 mg, 0.26 mmol)was added to the mixture at 0-5° C. The reaction mixture was stirredabout 15 min at 0-5° C., 50% H₃PO₂ (17 mg, 0.26 mmol) was added. Themixture was stirred at room temperature overnight, quenched withaq.NaHCO₃ solution, extracted with ethyl acetate. The combined organiclayer was concentrated under vacuum to give a residue which was purifiedwith chromatography (ethyl acetate/petroleum ether=0.06) to give7-bromobenzo[d]thiazole (10 mg, 30%).

The title compound (20 mg) was prepared from 7-bromobenzo[d]thiazoleaccording to protocol P. LCMS (0.05% TFA): [M+1]⁺194.1. ¹H-NMR (CDCl₃,400 MHz): δ 9.05 (s, 1H), 8.10 (d, 1H, J=6.8 Hz), 7.53 (m, 1H), 7.39 (d,1H, J=6.8 Hz), 3.96 (s, 2H).

4-Bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine

2-aminothiophene-3-carbonitrile (2.75 g, 22.1 mmol) in formic acid (15ml) and concentrated sulfuric acid (1 ml) was heated in a microwave for15 min at 100° C. The solution was diluted with water, filtered, and thefiltrated was concentrated under reduced pressure to yieldthieno[2,3-d]pyrimidin-4(3H)-one as a purple film. Method [6] retentiontime 2.09 min by HPLC (M+ 153).

Thieno[2,3-d]pyrimidin-4(3H)-one, sodium acetate (20.92 g, 255 mmol),and bromine (3.0 ml, 58.2 mmol) in glacial acetic acid (100 ml) wasstirred for 24 h. A second portion of bromine (10 ml, 194 mmol) wasadded and the heterogeneous mixture heated to reflux for 3 h, thencooled to ambient temperature. The mixture was diluted with saturatedaqueous sodium sulfite and extracted with methylene chloride. Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated under reduced pressure. The residue was flashchromatographed with 99:1:0.1, 49:1:0.1, 24:1:0.1, and 23:2:0.2methylene chloride:methanol:concentrated ammonium hydroxide as theeluant to afford 1.96 g (29% yield over two steps) of5,6-dibromothieno[2,3-d]pyrimidin-4(3H)-one as a yellow solid. Method[8] retention time 6.19 min by HPLC (M+ 309, 311, and 313).

Zinc dust (210 mg, 3.21 mmol) was added to a solution of5,6-dibromothieno[2,3-d]pyrimidin-4(3H)-one (910 mg, 2.94 mmol) inglacial acetic acid (8 ml) and water (2 ml). After stirring for 4 h, asecond portion of zinc dust (214 mg, 3.27 mmol) was added and theheterogeneous mixture was placed into a preheated oil bath at 60° C. Theheterogeneous mixture became a clear solution in 30 min. The solutionwas diluted with water and extracted with ethyl acetate. The combinedorganic extracts were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to afford5-bromothieno[2,3-d]pyrimidin-4(3H)-one as a white solid. Method [8]retention time 2.68 min by HPLC (M+ 231 and 233).

5-Bromothieno[2,3-d]pyrimidin-4(3H)-one in phosphorus(V) oxychloride (10ml) was heated in a microwave at 100° C. for 30 min. The solution wasconcentrated under reduced pressure to yield5-bromo-4-chlorothieno[2,3-d]pyrimidine. Method [8] retention time 8.72min by HPLC (M+ 249, 251, and 253) major peak intensities.

5-Bromo-4-chlorothieno[2,3-d]pyrimidine and hydrazine monohydrate (2 ml,41.2 mmol) in absolute ethanol (10 ml) was heated to 75° C. Afterstirring for 1 h, the solution was concentrated to yield5-bromo-4-hydrazinylthieno[2,3-d]pyrimidine. Method [8] retention time0.80 min by HPLC (M+ 245 and 247).

5-bromo-4-hydrazinylthieno[2,3-d]pyrimidine and triethylorthoformate (40ml) in ethanol (10 ml) was placed into a preheated oil bath at 100° C.for 24 h. The solution was concentrated and the residue was flashchromatographed with 9:1, 4:1, and 7:3 methylene chloride:ethyl acetateas the eluant to afford 578 mg (38% yield over 4 steps) of9-bromothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine as a yellow solid.Method [8] retention time 4.17 min by HPLC (M+ 255 and 257).

9-Bromothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (551 mg, 2.16 mmol)and N-methylethane-1,2-diamine (1 ml, 11.3 mmol) in methanol (20 ml) wasplaced into a preheated oil bath at 60° C. After stirring for 15 min,the solution was diluted with saturated ammonium chloride and extractedwith methylene chloride. The combined organic extracts were dried overmagnesium sulfate, filtered, and concentrated under reduced pressure toafford 525 mg (99% yield) of4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine as a brown solid.Method [8] retention time 2.25 min by HPLC (M+ 245 and 247).

EXAMPLE 1 Synthesis of Thiophene Triazoles 1.1 Synthesis ofN-(2-(1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(1)

1.1.1 3-(2-(Naphthalen-1-yl)acetamido)thiophene-2-carboxylic acid

Methyl 3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylate (210 mg,0.647 mmol) was dissolved in THF/H₂O (2.5 mL, 4/1, v/v). Sodiumhydroxide (129 mg, 3.22 mmol) was added and the reaction mixture wasstirred at 50° C. for 20 h. The resulting solution was acidified with10% aqueous HCl and extracted with ethyl acetate. The organic phase wasseparated, dried (Na₂SO₄), filtered and concentrated under vacuum togive 3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylic acid.Retention time=1.962 min, method [1], MS(ESI) 312.1 (M+H).

1.1.2. 3-(2-(Naphthalen-1-yl)acetamido)thiophene-2-carboxamide

3-(2-(Naphthalen-1-yl)acetamido)thiophene-2-carboxylic acid (151 mg,0.485 mmol) was dissolved in thionyl chloride (2 mL) and the resultingsolution was stirred at 60° C. for 30 minutes. The resulting solutionwas concentrated under vacuum and the residue was dissolved inacetonitrile (2 mL). Concentrated aqueous ammonium hydroxide (2 mL) wasadded to the resulting solution and the mixture was stirred at roomtemperature for 2 hr. The solution was concentrated to 1 mL, dilutedwith ethyl acetate and washed with brine. The organic phase wasseparated and dried (Na₂SO₄), filtered, concentrated under vacuum andthe residue was purified on a silica gel column (eluant hexane/ethylacetate, 8/2 to 1/1) to give3-(2-(naphthalen-1-yl)acetamido)-thiophene-2-carboxamide (81 mg, 0.26mmol, 54%). Retention time (min)=4.917, method [7], MS(ESI) 311.1 (M+H).

1.1.3.N-(2-(1H-1,2,4-Triazol-5-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide

The title compound was prepared from3-(2-naphthalen-1-yl)acetamido)thiophene-2-carboxamide (104 mg, 0.335mmol) according to protocol C. Method [7] retention time (min)=5.105,MS(ESI) 335.1 (M+H); ¹H-NMR (300 MHz, CDCl₃): δ 10.43 (s, 1H), 8.15 (d,J=5.4 Hz, 1H), 8.05-8.08 (m, 1H), 7.90-7.94 (m, 1H), 7.80 (s, 1H),7.29-7.60 (m, 4H), 7.27 (s, 1H), 4.32 (s, 2H).

1.2 Synthesis ofN-(2-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(2)

The title compound was prepared from3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxamide (72 mg, 0.23mmol) according to protocol D. Retention time (min=4.919, method [7],MS(ESI) 349.0 (M+H); ¹H-NMR (300 MHz, CDCl₃): δ 10.32 (s, 1H), 8.16 (d,J=5.5 Hz, 1H), 8.08-8.11 (m, 1H), 7.87-7.92 (m, 2H), 7.52-7.61 (m, 4H),7.24 (d, J=5.5 Hz, 1H), 4.28 (s, 2H), 2.32 (s, 3H).

1.3. Synthesis ofN-(2-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(3)

The title compound was prepared from3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxamide (71 mg, 0.22mmol) using protocol D except that methyl hydrazine was used instead ofhydrazine. The crude product was purified by preparative HPLC to giveN-(2-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide.Retention time (min)=6.636, method [7], MS(ESI) 363.1 (M+H); ¹H-NMR (300MHz, CDCl₃): δ 11.20 (s, 1H), 8.30 (d, J=5.5 Hz, 1H), 8.12 (d, J=8.2 Hz,1H), 7.5-7.91 (m, 2H), 7.48-7.62 (m, 4H), 7.40 (d, J=5.5 Hz, 1H), 4.27(s, 2H), 3.96 (s, 3H), 2.19 (s, 3H).

1.4 Synthesis ofN-(2-(1-methyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(4)

The title compound was prepared from3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxamide (104 mg, 0.335mmol) according to protocol C except that methyl hydrazine was usedinstead of hydrazine. The reaction mixture was purified by preparativeHPLC to giveN-(2-(1-methyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide.Retention time (min)=6.494, method [7], MS(ESI) 349.1 (M+H); ¹H-NMR (300MHz, CDCl₃): δ 11.2 (s, 1H), 8.30 (d, J=5.5 Hz, 1H), 7.88-8.06 (m, 3H),7.42-7.59 (m, 5H), 7.41 (d, J=5.5 Hz, 1H), 4.30 (s, 2H), 3.98 (s, 3H).

Synthesis of2-(4-Methoxyphenyl)-N-(2-(3-methyl-1H-1,2,4-triazol-5-yl)thiophene-3-yl)acetamide(5)

1.5.1. Methyl 3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylate

The title compound was prepared from 2-(4-methoxyphenyl)acetic acid(3.18 g, 19.2 mmol) and methyl 3-aminothiophene-2-carboxylate (3.02 g,19.2 mmol) according to protocol B. Retention time (min)=2.143, method[1], MS(ESI) 306.1 (M+H).

1.5.2. 3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylic acid

Methyl 3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylate (5.7 g,18.7 mmol) was dissolved in THF/H₂O (40 mL, 4/1, v/v). Sodium hydroxide(2.24 g, 56.1 mmol) was added and the reaction mixture was stirred at60° C. for 8 h. The resulting solution was acidified with 10% aqueousHCl and extracted with ethyl acetate. The organic phase was separated,dried (Na₂SO₄), filtered and concentrated under vacuum to give3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylic acid. Retentiontime (min)=1.678, method [1], MS(ESI) 292.1 (M+H).

1.5.3. 3-(2-(4-Methoxyphenyl)acetamido)thiophene-2-carboxamide

The title compound was prepared from3-(2-(4-methoxyphenyl)acetamido)-thiophene-2-carboxylic acid (1.51 g,4.95 mmol) according to protocol B (504 mg, 1.73 mmol, 35%). Retentiontime (min)=1.446, method [1], MS(ESI) 329.1 (M+H).

1.5.4.2-(4-Methoxyphenyl)-N-(2-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)acetamide

The title compound was prepared from3-(2-(4-methoxyphenyl)acetamido)-thiophene-2-carboxamide (204 mg, 0.703mmol) according to protocol D. Retention time (min)=3.893, method [7],MS(ESI) 329.1 (M+H); ¹H NMR (300 MHz, CDCl₃): δ 10.33 (s, 1H), 8.10 (d,J=5.4 Hz, 1H), 7.27-7.33 (m, 3H), 6.90 (d, J=9.2 Hz, 2H), 3.81 (s, 3H),3.71 (s, 2H), 2.54 (s, 3H).

1.6. Synthesis ofN-(2-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(quinolin-5-yl)acetamide(6)

The title compound can be made from3-(2-(quinolin-5-yl)acetamido)thiophene-2-carboxamide (see Example1.27.1, below) using protocol D.

1.7. Synthesis ofN-(2-(1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(7)

The title compound was prepared from3-(2-(4-methoxyphenyl)acetamido)-thiophene-2-carboxamide (Example 1.5.3,271 mg, 0.933 mmol) according to protocol C. Retention time (min)=3.754,method [7], MS(ESI) 315.1 (M+H); ¹H-NMR (300 MHz, CDCl₃): δ 10.48 (s,1H), 8.12-8.16 (m, 2H), 7.28-7.33 (m, 3H), 6.97 (d, J=8.3 Hz, 2H), 3.87(s, 3H), 3.79 (s, 2H).

1.8 Synthesis ofN-(2-(1H-1,2,4-Triazol-1-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(8)

1.8.1. 1-(3-Nitrothiophen-2-yl)-1H-1,2,4-triazole

1H-1,2,4-triazole (582 mg, 843 mmol), 2-chloro-3-nitrothiophene (1.15 g,7.03 mmol) and potassium t-butoxide (944 mg, 8.43 mmol) were dissolvedin DMF (30 mL). The resulting solution was stirred at 90° C. for 2 h,after which the reaction mixture was cooled to room temperature anddiluted with Et₂O. The solution was washed with brine and the organicphase was separated, dried Na₂SO₄), filtered, concentrated under vacuumto give 1-(3-nitrothiophen-2-yl)-1H-1,2,4-triazole. Retention time(min)=1.073, method [1], MS(ESI) 197.0 (M+H).

1.8.2. 2-(1H-1,2,4-Triazol-1-yl)thiophen-3-amine

A mixture of 1-(3-nitrothiophen-2-yl)-1H-1,2,4-triazole (462 mg, 2.35mmol), iron (1.31 g, 23.5 mmol) and ammonium chloride (163 mg, 3.06mmol) in water (5 mL) was stirred at 100° C. for 18 h. The resultingsuspension was filtered through a pad of diatomaceous earth and thefiltrate was basified with aqueous NaOH. The aqueous solution wasextracted with methylene chloride and the organic phase separated, dried(Na₂SO₄), filtered and concentrated under vacuum to give2-(1H-1,2,4-triazol-1-yl)thiophen)-3-amine (314 mg, 1.89 mmol, 80%).Retention time (min)=0.454, method [1], MS(ESI) 167.0 (M+H).

1.8.3.N-(2-(1H-1,2,4-Triazol-1-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide

The title compound was prepared from 2-(4-methoxyphenyl)acetic acid (233mg, 1.41 mmol) and 2-(1H-1,2,4-triazol-1-yl)thiophen-3-amine (234 mg,1.41 mmol) according to protocol B. Retention time (min)=2.847, method[7], MS(ESI) 315.2 (M+H); ¹H-NMR (300 MHz, CDCl₃): δ 9.27 (s, 1H), 8.31(s, 1H), 7.99 (d, J=5.3 Hz, 1H), 7.83 (s, 1H), 7.22 (d, J=8.1 Hz, 2H),7.09 (d, J=5.3 Hz, 1H), 6.94 (d, J=8.1 Hz, 2H), 3.87 (s, 3H), 3.72 (s,2H).

1.9. Synthesis of2-(4-methoxyphenyl)-N-(4-methyl-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2yl)acetamide(9)

1.9.1. 2-(2-(4-Methoxyphenyl)acetamido-4-methylthiophene-3-carboxamide

The title compound was prepared from 2-(4-methoxyphenyl)acetic acid(1.21 g, 7.22 mmol) and 2-amino-4-methylthiophene-3-carboxamide (1.12 g,7.22 mmol) according to protocol B. Retention time (min)=1.903, method[1], MS(ESI) 305.0 (M+H).

1.9.2.2-(4-Methoxyphenyl)-N-(4-methyl-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)acetamide

The title compound was prepared from2-(2-(4-methoxyphenyl)acetamido)-4-methylthiophene-3-carboxamide (604mg, 1.98 mmol) according to protocol D. Retention time (min=4.530,method [7], MS(ESI) 343.1 (M+H); ¹H-NMR (300 MHz, CDCl₃): δ 11.95 (s,1H), 7.33 (d, J=9.1 Hz, 2H), 6.95 (d, J=9.1 Hz, 2H), 6.52 (s, 1H), 3.83(s, 3H), 3.82 (s, 2H), 2.49 (s, 3H), 2.34 (s, 3H).

1.10. Synthesis ofN-(2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(10)

1.10.1. 2-(3-Nitrothiophen-2-yl)-2H-1,2,3-triazole

A solution of 1,2,3-triazole (430 mg, 6.23 mmol), 2-chloro-3-nitrophene(1.02 g, 6.23 mmol) and potassium t-butoxide (838 mg, 7.48 mmol) in DMF(20 mL) was stirred at 90° C. for 4 h, after which the reaction mixturewas cooled to room temperature and diluted with Et₂O. The solution waswashed with brine and the organic phase was separated, dried (Na₂SO₄),filtered, concentrated under vacuum and purified by silica gel columnchromatography (eluant hexane/ethyl acetate, 8/2 to 1/1) to give a 1:1mixture of 2-(3-nitrothiophen-2-yl)-2H-1,2,3-triazole and1-(3-nitrothiophen-2-yl)-1H-1,2,3-triazole (1.08 g, 5.55 mol, 89%).Retention time (min)=1.256 and 1.701, method [1], MS(ESI) 197.0 (M+H).

1.10.2. 2-(2H-1,2,3-Triazol-2-yl)thiophen-3-amine

The title compound was prepared from2-(3-nitrothiophen-2-yl)-2H-1,2,3-triazole and1-(3-nitrothiophen-2-yl)-1H-1,2,3-triazole (514 mg, 2.61 mmol) accordingto protocol F to give a 1/1 mixture of2-(2H-1,2,3-triazol-2-yl)thiophen-3-amine and1-(1H-1,2,3-triazol-2-yl)thiophen-3-amine (431 mg, 2.61 mmol,quantitative). Retention time (min)=0.581 and 1.035, method [1], MS(ESI)167.0 (M+H).

1.10.3.N-(2-(2H-1,2,3-Triazol-2-yl)thiophen-3-yl)-2-(4-methoxyphenyl)-acetamide

The title compound was prepared from (2-(4-methoxyphenyl)acetic acid(1.21 g, 7.22 mmol) and a 1:1 mixture of2-(2H-1,2,3-triazol-2-yl)thiophen-3-amine and1-(1H-1,2,3-triazol-2-yl)thiophen-3-amine (431 mg, 2.61 mmol) accordingto protocol B to giveN-(2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide.Retention time (min)=5.712, method [7], MS(ESI) 315.0 (M+H); ¹H-NMR (300MHz, CDCl₃): δ 9.99 (s, 1H), 8.06 (d, J=6.4 Hz, 1H), 7.67 (s, 2H),7.28-7.31 (m, 2H), 7.02 (d, J=5.7 Hz, 1H), 6.98 (d, J=9.1 Hz, 2H), 3.88(s, 3H), 3.76 (s, 2H).

1.11. Synthesis ofN-(2-(3-Cyclopropyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(11)

1.11.1.N-(2-(Hydrazinecarbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)-acetamide

Hydrazine monohydrate (0.825 mL, 17.1 mmol) was added to a solution ofmethyl 3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylate (3.48 g,11.4 mmol) in ethanol (40 mL) and the resulting solution was stirred atroom temperature for 24 h. The mixture was diluted with brine andextracted with ethyl acetate. The organic phase was separated, dried(Na₂SO₄), filtered, concentrated under vacuum and purified on a silicagel column (eluant hexane/ethyl acetate, 1/1 to 1/9) to giveN-(2-(hydrazine-carbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(1.71 g, 5.60 mmol, 49%). Retention time (min)=1.300, method [1],MS(ESI) 306.0 (M+H).

1.11.2.N-(2-(3-Cyclopropyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide

A mixture ofN-(2-(hydrazinecarbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide (101mg, 0.30 mmol), cyclopropylcarbamidine hydrochloride (47 mg, 0.39 mmol)and sodium methoxide (39 mg, 0.72 mmol) in ethanol (3 mL) was stirred at120° C. for 17 h. The mixture was diluted with brine and extracted withethyl acetate. The organic phase was separated, dried (Na₂SO₄),filtered, concentrated under vacuum and purified by preparative HPLC togiveN-(2-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide.Retention time (min)=5.578, method [7], MS(ESI) 354.43 (M+H); ¹H-NMR(300 MHz, CDCl₃): δ 10.48 (s, 1H), 8.11 (d, J=5.6 Hz, 1H), 7.25-7.32 (m,3H), 6.94 (d, J=8.8 Hz, 2H), 3.83 (s, 3H), 3.74 (s, 2H), 1.98-2.03 (m,1H), 1.07-1.17 (m, 4H).

The following compounds were synthesized fromN-(2-(hydrazinecarbonyl)-thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(Example 1.11.1) and the appropriate amidine using the proceduredescribed above in Example 1.11.2:

1.12.N-(2-(3-Ethyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(12)

Propionimidamide hydrochloride was used. Retention time (min)=4.404,method [7], MS(ESI) 343. 1 (M+H); ¹H-NMR (300 MHz, CDCl₃): δ 10.54 (s,1H), 8.14 (d, J=5.4 Hz, 1H), 7.24-7.34 (m, 3H), 6.92 (d, J=8.3 Hz, 2H),3.84 (s, 3H), 3.76 (s, 2H), 2.79 (q, J=7.8 Hz, 2H), 1.36 (t, J=7.8 Hz,3H).

1.13.N-(2-(3-tert-Butyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(13)

Pivalimidamide hydrochloride was used. Retention time (min)=6.103,method [7], MS(ESI) 371.1 (M+H); ¹H-NMR (300 MHz, CDCl₃): δ 10.76 (s,1H), 8.05 (d, J=5.4 Hz, 1H), 7.26-7.31 (m, 3H), 6.88 (d, J=8.8 Hz, 2H),3.76 (s, 3H), 3.75 (s, 2H), 1.44 (s, 9H).

1.14.2-(4-Methoxyphenyl)-N-(2-(3-(tetrahydrofuran-2-yl)-1H-1,2,4-triazol-5-yl)thiophen-3-yl)acetamide(14)

Tetrahydrofuran-2-carboximidamide acetate was used. Retention time(min)=4.585,method [7], MS(ESI) 385.1 (M+H); ¹H-NMR (300 MHz, CDCl₃): δ10.37 (s, 1H), 8.14 (d, J=5.4 Hz, 1H), 7.25-7.32 (m, 3H), 6.94 (d, J=8.8Hz, 2H), 5.08 (dd, J=7.6, 5.8 Hz, 1H), 3.96-4.09 (m, 2H), 3.84 (s, 3H),3.80 (s, 2H), 2.41-2.45 (m, 1H), 1.95-2.10 (m, 3H).

1.15.2-(4-Methoxyphenyl)-N-(2-(3-trifluoromethyl)-1H-1,2,4-triazol-5-yl)thiophen-3-yl)acetamide(15)

2,2,2-Trifluoroacetimidamide was used. Retention time (min)=6.744,method [7], MS(ESI) 383.1 (M+H); ¹H-NMR (300 MHz, CDCl₃): δ 10.38 (s,1H), 8.11 (d, J=5.4 Hz, 1H), 7.28-7.34 (m, 3H), 6.90 (d, J=8.8 Hz, 2H),3.81 (s, 3H), 3.79 (s, 2H).

1.16. Synthesis ofN-(4-methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1-(2H)-yl)acetamide(16)

1.16.14-Methyl-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)-thiophene-3-carboxamide

4-Methyl-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxamidewas prepared from 2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid(0.49 g, 2.38 mmol) and 2-amino-4-methylthiophene-3-carboxamide (0.37 g,2.38 mmol) according to protocol B Retention time (min)=3.405, method[1], MS(ESI) 344.0 (M+H).

1.16.2.N-(4-Methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide

N-(4-Methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamidewas prepared from4-methyl-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxamide(107 mg, 0.315 mmol) according to protocol C. Retention time(min)=4.052, method [7], MS(ESI) 368.1 (M+H); ¹H-NMR (300 MHz, CDCl₃): δ12.40 (s, 1H), 7.95 (s, 1H), 7.21-7.28 (m, 2H), 6.99-7.08 (m, 2H), 6.56(s, 1H), 4.91 (s, 2H), 3.09 (dd, J=8.2, 6 Hz, 2H), 2.91 (dd, J=8.2, 6Hz, 2H), 2.51 (s, 3H).

1.17. Synthesis ofN-(4-Methyl-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide(17)

1.17.1 Methyl4-methyl-2(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxylate

The title compound was prepared from2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (0.43 g, 2.09 mmol)and methyl 2-amino-4-methylthiophene-3-carboxylate (0.358 g, 2.09 mmol)according to protocol B. Retention time (min)=6.895, method [7], MS(ESI)359.1 (M+H).

1.17.2.N-(3-(Hydrazinecarbonyl)-4-methylthiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide

Hydrazine monohydrate (0.059 mL, 1.23 mmol) was added to a solution ofmethyl4-methyl-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxylate(221 mg, 0.616 mmol) in ethanol (2 mL) and the resulting solution wasstirred at 50° C. for 24 h. The mixture was diluted with brine andextracted with ethyl acetate. The organic phase was separated, dried(Na₂SO₄), filtered, concentrated under vacuum to giveN-(3-(hydrazinecarbonyl)-4-methylthiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-acetamide(174 mg, 0.485 mmol, 79%). Retention time (min)=1.435, method [1],MS(ESI) 359.1 (M+H).

1.17.3.N-(4-Methyl-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide

The title compound was prepared from acetimidamide hydrochloride (55 mg,0.590 mmol) andN-(3-hydrazinecarbonyl)-4-methylthiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide(141 mg, 0.393 mmol) according to the procedure of Example 1.11.2,above. Retention time (min)=4.106, method [7], MS(ESI) 382.1 (M+H);¹H-NMR (300 MHz, CDCl₃): δ 12.07 (s, 1H), 7.23-7.31 (m, 2H), 7.05-7.23(m, 2H), 6.57 (s, 1H), 4.86 (s, 2H), 3.02-3.07 (m, 2H), 2.84-2.87 (m,2H), 2.41 (s, 3H), 2.39 (s, 3H).

1.18. Synthesis of2-(4-methoxyphenyl)-N-(2-(3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)thiophen-3-yl)acetamide(18)

The title compound was prepared from pyridine-4-carboximidamidehydrochloride (157 mg, 1.00 mmol) andN-(2-(hydrazinecarbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(Example 1.11.1., 204 mg, 0.668 mmol) according to the proceduredescribed in Example 1.11.2., above. Retention time (min)=2.511, method[7], MS(ESI) 359.1 (M+H). ¹H-NMR (300 MHz, DMSO-d₆): δ 10.52 (s, 1H),8.87 (d, J=4.5 Hz, 2H), 8.08-8.16 (m, 2H), 7.94 (d, J=5.0 Hz, 1H),7.67-7.70 (m, 1H), 7.31 (d, J=8.6 Hz, 2H), 7.88 (d, J=8.6 Hz, 2H), 3.8(s, 2H), 3.67 (s, 3H).

1.19. Synthesis ofN-(2-(3-amino-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(19)

The title compound was prepared fromN-(2-(hydrazinecarbonyl)(thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(Example 1.11.1., 152 mg, 0.497 mmol) and S-methylisothiouronium sulfate(276 mg, 0.995 mmol) according to the procedure described in Example1.11.2 except that sodium hydroxide was used (rather than sodiummethoxide). Retention time (min)=2.324, method [7], MS(ESI) 330.0 (M+H);¹H-NMR (300 MHz, CDCl₃): δ 9.95 (s, 1H), 8.07 (d, J=5.7 Hz, 1H),7.26-7.29 (m, 3H), 6.94 (d, J=7.9 Hz, 2H), 3.83 (s, 3H), 3.74 (s, 2H).

1.20. Synthesis ofN-(4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide(20)

1.20.1. Methyl4-bromo-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxylate

The title compound was prepared from2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (447 mg, 2.18 mmol)and methyl 2-amino-4-bromothiophene-3-carboxylate (516 mg, 2.18 mmol)according to protocol A. Retention time (min)=2.528, method [1], MS(ESI)423.0 (M+H).

1.20.2. Methyl4-chloro-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxylate

The title compound was prepared from methyl4-bromo-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxylate(148 mg, 0.35 mmol) according to protocol G. Retention time (min)=2.540,method [1], MS(ESI) 379.0 (M+H).

1.20.3.4-Chloro-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)-thiophene-3-carboxamide

The title compound was prepared from methyl4-chloro-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxylate(254 mg, 0.67 mmol) according to protocol H. Retention time (min)=2.034,method [1], MS(ESI) 364.0 (M+H).

1.20.4.N-(4-Chloro-3(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide

The title compound was prepared from4-chloro-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxamide(218 mg, 0.601 mmol) according to protocol C. Retention time(min)=4.171, method [7], MS(ESI) 388.0 (M+H); ¹H-NMR (300 MHz, CDCl₃): δ7.85 (s, 1H), 7.21-7.30 (m, 2H), 7.07 (dd, J=7.4, 7.3 Hz, 1H), 6.94 (d,J=8.3 Hz, 1H), 6.83 (s, 1H), 4.93 (s, 2H), 3.09-3.14 (m, 2H), 2.89-2.94(m, 2H).

1.21. Synthesis ofN-(3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1-(2H)-yl)acetamide(21)

N-(3-(1H-1,2,4-Triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamidewas isolated during the purification ofN-(4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide(1.20.4. The des-chlorothiophene was likely formed during the conversionof4-bromo-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxylateto methyl4-chloro-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxylate.Retention time (min)=3.296, method [7], MS(ESI) 354.0 (M+H); ¹H-NMR (300MHz, CDCl₃): δ 7.99 (s, 1H), 7.23-7.29 (m, 3H), 7.06-7.10 (m, 2H), 6.88(d, J=6.3 Hz, 1H), 4.92 (s, 2H), 3.07-3.10 (m, 2H), 2.92-2.95 (m, 2H).

1.22. Synthesis ofN-(4-chloro-3-(1H)-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(isoquinolin-5-yl)acetamide(22)

1.22.1. Methyl4-bromo-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate

The title compound was prepared from 2-(isoquinolin-5-yl)acetic acid(427 mg, 2.18 mmol) and methyl 2-amino-4-bromothiophene-3-carboxylate(514 mg, 2.18 mmol) according to protocol A. Retention time (min)=1.634,method [1], MS(ESI) 405.0 (M+H).

1.22.2. Methyl4-chloro-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate

The title compound was prepared from methyl4-bromo-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate (124mg, 0.306 mmol) according to protocol G. Retention time (min)=1.609,method [1], MS(ESI) 361.0 (M+H).

1.22.3.4-Chloro-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxamide

The title compound was prepared from methyl4-chloro-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate (110mg, 0.306 mmol) according to protocol H. Retention time (min)=1.139,method [1], MS(ESI) 346.0 (M+H).

1.22.4N-(4-Chloro-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(isoquinolin-5-yl)acetamide

The title compound was prepared from4-chloro-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxamide (104mg, 0.306 mmol) according to protocol C. Retention time (min)=1.570,method [7], MS(ESI) 370.1 (M+H); ¹H-NMR (300 MHz, CD₃OD): δ 9.62 (s,1H), 8.57 (d, J=6.1 Hz, 1H), 8.42 (d, J=8.8 Hz, 1H), 8.35 (d, J=6.1 Hz,1H), 8.18 (d, J=7.0 Hz, 1H), 8.09 (bs, 1H), 8.00 (dd, J=8.4, 7.3 Hz,1H), 6.95 (s, 1H), 4.51 (s, 2H).

1.23. Synthesis ofN-(4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamide(23)

1.23.1. Methyl4-bromo-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxylate

Methyl 4-bromo-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxylate wasprepared from 2-(quinolin-5-yl)acetic acid (427 mg, 2.18 mmol) andmethyl 2-amino-4-bromothiophene-3-carboxylate (514 mg, 2.18 mmol)according to protocol A. Retention time (min)=1.660, method [1], MS(ESI)405.0 (M+H).

1.23.2 Methyl4-chloro-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxylate

Methyl 4-chloro-2-(2-quinolin-5-yl)acetamido)thiophene-3-carboxylate wasprepared from methyl4-bromo-2(2-(quinolin-5-yl)acetamido)thiophene-3-carboxylate (350 mg,0.86 mmol) according to protocol G. Retention time (min)=1.629, method[1], MS(ESI) 361.0 (M+H).

1.23.3. 4-Chloro-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxamide

4-Chloro-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxamide wasprepared from methyl4-chloro-2-(2-quinolin-5-yl)acetamido)thiophene-3-carboxylate (151 mg,0.418 mmol) according to protocol H. Retention time (min)=1.151, method[1], MS(ESI) 346.0 (M+H).

1.23.4.N-(4-Chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamide

N-(4-Chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamidewas prepared from4-chloro-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxamide (78 mg,0.225 mmol) according to protocol I. Retention time (min)=1.429, method[7], MS(ESI) 370.0 (M+H); ¹H-NMR (300 MHz, CD₃OD): δ 9.15-9.19 (m, 2H),8.26 (d, J=8.3 Hz, 1H), 8.11-8.17 (m, 2H), 7.95-8.01 (m, 2H), 6.95 (s,1H), 4.57 (s, 2H).

1.24. SynthesisN-(2-(1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetamide(24)

1.24.1.3-(2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)acetamido)thiophene-3-carboxamide

The title compound was prepared from2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetic acid (450 mg) and2-aminothiophene-3-carboxamide (345 mg) according to protocol B. Thecrude product mixture was taken directly to the next reaction withoutfurther purification. Method [1], MS(ESI) 319.2 [M+H], Retentiontime=1.496 min.

1.24.2.N-(2-(1H-1,2,4-Triazol-5-yl)thiophen-3-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetamide

The title compound was prepared from3-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetamido)thiophene-2-carboxamideaccording to protocol C. The crude product was purified via preparativeHPLC to giveN-(2-(1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetamide;Method [7], MS(ESI) 343.0 [M+H], Retention time=3.39 min; ¹H-NMR (300MHz, CDCl₃): δ 10.51 (s, 1H), 8.21 (s, 1H), 8.11 (d, J=5.5 Hz, 1H),7.28-7.26 (m, 1H), 7.31 (d, J=5.5 Hz, 1H), 6.93-6.83 (m, 2H), 4.27 (s,4H), 3.73 (s, 2H).

1.25. Synthesis ofN-(4-methyl-3-(1H-1,2,4-triazol-5-yl)thiophene-2-yl)-2-(quinolin-5-yl)acetamide(25)

1.25.1. 4-Methyl-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxamide

The title compound was prepared from 2-(quinolin-5-yl)acetic acid and3-amino-4-methylthiophene-2-carboxamide using protocol B. Method [1],MS(ESI) 326.0 [M+H], Retention time=0.767 min.

1.25.2.N-(4-Methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamide

The title compound was prepared from4-methyl-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxamide usingprotocol C. The crude product was purified via preparative HPLC to giveN-(4-methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamide.Method [7], MS(ESI) 350.1 [M+H], Retention time=1.43 min; ¹H-NMR (300MHz, CDCl₃): δ 11.16 (s, 1H), 9.02 (d, J=4.94 Hz, 1H), 8.96 (d, J=8.2Hz, 1H), 8.6 (d, J=8.2 Hz, 1H), 8.13-8.08 (m, 1H), 7.92 (s, 1H),7.90-7.84 (m, 2H), 6.51 (s, 1H), 4.45 (s, 2H), 2.44 (s, 3H).

1.26. Synthesis of2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(2-(3-methyl-1H-1,2,4-triazol-5-yl)(thiophen-3-yl)acetamide(26)

The title compound was prepared from2-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetamido)thiophene-3-carboxamideusing protocol D except that the DMF was also used in the DMA-DMA stepwith heating to 95° C. (rather than 110° C.) and the hydrazine step washeated at 95° C. (rather than 90° C.). The product was purified viapreparative HPLC to give2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(2-(3-methyl-1H-1,2,4-triazol-5-l)thiophen-3-yl)acetamide;Method [7], MS(ESI) 357.1 [M+H], Retention time=3.56 min; ¹H-NMR (300MHz, CDCl₃): δ 10.33 (s, 1H), 8.06 (d, J=5.5 Hz, 1H), 7.29 (d, J=5.6 Hz,1H), 7.27-7.26 (m, 1H), 6.88-6.86 (m, 1H), 6.84-6.82 (m, 1H), 4.22 (s,4H), 3.70 (s, 2H), 2.51 (s, 3H).

1.27. SynthesisN-(2-(1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(quinolin-5-yl)acetamide(27)

1.27.1. 3-(2-(Quinolin-5-yl)acetamido)thiophene-2-carboxamide

The title compound was prepared from 2-(quinolin-5-yl)acetic acid and3-aminothiophene-2-carboxamide using protocol B. Method [1], MS(ESI)312.1 [M+H], Retention time=0.351 min.

1.27.2N-(2-(1H-1,2,4-Triazol-5-yl)thiophen-3-yl)-2-(quinolin-5-yl)acetamide

This compound was prepared from2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxamide using protocol Cand was purified via preparative HPLC. Method [9], MS(ESI) 336.0 [M+H],rt=6.526 min; ¹H-NMR (300 MHz, CDCl₃) δ 9.30 (s, 1H), 9.05 (d, J=8.24Hz, 1H), 8.98 (d, J=4.95 Hz, 1H), 8.63 (d, J=8.8 Hz, 1H), 8.20-8.15 (m,1H), 8.06 (s, 1H), 8.04 (s, 1H), 7.99-7.91 (m, 3H), 4.47 (s, 2H).

1.28. Synthesis ofN-(4-methyl-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamide(28)

This compound was made from4-methyl-2-(2-(quinolin-5-yl)acetamido)-thiophene-3-carboxamide usingprotocol D. The product was purified via preparative HPLC to giveN-(4-methyl-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamide.Method [9], MS(ESI) 364.1 [M+H], Retention time=8.72 min; ¹H-NMR (300MHz, CDCl₃): δ 10.76 (s, 1H), 9.04 (s, 1H), 9.0 (d, J=3.85 Hz, 1H), 8.61(d, J=8.8 Hz, 1H), 8.14 (dd, J=8.8, 7.7 Hz, 1H), 7.94-7.89 (m, 2H), 6.49(s, 1H), 4.46 (s, 2H), 2.41 (s, 3H), 2.40 (s, 3H).

1.29. Synthesis ofN-(4-methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinoxalin-5-yl)acetamide(29)

1.29.1. Tert-butyl 2-(quinoxalin-5-yl)acetate

The title compound was prepared 5-bromoquinoxaline (500 mg, 1.0 eq)according to protocol P to give tert-butyl 2-(quinoxalin-5-yl)acetate.Method [1], MS(ESI) 245.1 [M+H], Retention time=2.305 min.

1.29.2. 4-Methyl-2-(2-(quinoxalin-5-yl)acetamido)thiophene-3-carboxamide

to a stirring mixture of tert-butyl 2-(quinoxaline-5-yl)acetate (200 mg)in HOAc (5 mL) was added 6N HCl (5 mL). The reaction mixture was warmedto 80° C. for 2 h. The crude product mixture was concentrated underreduced pressure to give 2-(quinoxalin-5-yl)acetic acid, which was usedin the next reaction without further purification. Method [1], MS(ESI)189.0 [M+H], Retention time=0.722 min.

The title compound was prepared from 2-(quinoxalin-5-yl)acetic acid and2-amino-4-methylthiophene-3-carboxamide using protocol B. Method [1],MS(ESI) 327.0 [M+H], Retention time=1.644 min.

1.29.3.N-(4-Methyl3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinoxalin-5-yl)acetamide

This analog was prepared from4-methyl-2-(2-(quinoxalin-5-yl)acetamido)-thiophene-3-carboxamide usingprotocol C. Method [7], MS(ESI) 351.1 [M+H], Retention time=3.36 min.¹H-NMR (300 MHz, CDCl₃): δ 11.84 (s, 1H), 8.90-8.87 (m, 2H), 8.21-8.18(m, 1H), 7.93-7.85 (m, 2H), 7.73 (s, 1H), 6.52 (s, 1H), 4.56 (s, 2H),2.45 (s, 3H).

1.30. Synthesis ofN-(4-methyl-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinoxalin-5-yl)acetamide(30)

This analog was made from4-methyl-2-(2-(quinoxalin-5-yl)acetamido)thiophene-3-carboxamide usingprotocol D except that the DMF was also used in the DMA-DMA step withheating to 95° C. (rather than 110° C.) and the hydrazine step washeated at 95° C. (rather than 90° C.). Method [7], MS(ESI) 365.1 [M+H],Retention time=3.58 min. ¹H-NMR (300 MHz, CDCl₃): δ 11.9 (s, 1H), 8.87(s, 2H), 8.17-8.14 (m, 1H), 7.92-7.83 (m, 2H), 6.50 (s, 1H), 4.53 (s,2H), 2.45 (s, 3H), 2.30 (s, 3H).

1.31. Synthesis ofN-(4-methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetamide(31)

1.31.1. Methyl 2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetate

1) To a stirring mixture of methyl 2-(4-hydroxyphenyl)acetate (1 g) inacetonitrile (12 mL, 0.5M) was added bromo-3-chloropropane (911 mg),K₂CO₃ (2.4 g). The reaction mixture was heated to 100° C. for 2 h, thenquenched with water and extracted with EtOAc. The organic layers weredried over MgSO4, filtered, and concentrated. The crude product was usedwithout further purification in the next reaction step. Method [1],MS(ESI) 243.0 [M+H], Retention time=2.50 min.

2) To a stirring mixture of crude methyl2-(4-(3-chloropropoxy)phenyl)acetate in acetonitrile (17 mL, 0.35 M) wasadded KI (192 mg), piperidine (1.5 g), and K₂CO₃ (2.4 g). The reactionmixture was heated to 100° C. for 2 h. It was then quenched with waterand extracted with EtOAc. The organic layers were dried over MgSO₄,filtered, and concentrated. The crude product was taken directly to thenext reaction. Method [1], MS(ESI) 292.1 [M+H], Retention time=1.330min.

1.31.2. 2-(4-(3-(Piperidin-1-yl)propoxy)phenyl)acetic acid

To a stirring mixture of methyl2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetate (570 mg) in HOAc (5 mL)was added 6N HCl (10 mL). The reaction mixture was warmed to 80° C. for2 h. The crude product mixture was concentrated under reduced pressureand directly taken to the next reaction without further purification.Method [1], MS(ESI) 278.1 [M+H], Retention time=0.666 min.

1.31.3.4-Methyl-2-(2-(4-(3-piperidin-1-yl)propoxy)phenyl)-acetamido)thiophene-3-carboxamide

Protocol X

To a stirring mixture of 2-(4-(3-(piperidin-1-yl)propoxy)phenyl)aceticacid (800 mg) in DMF/DCM (6 mL, 1:1) was added triethylamine (1.2 mL),DMAP (180 mg), 2-amino-4-methylthiophene-3-carboxamide (440 mg), andEDCl (1.1 g). The reaction mixture was stirred at rt overnight, quenchedwith saturated NaHCO₃ solution and extracted with EtOAc. The organiclayers were dried over MgSO₄, filtered, and concentrated under reducedpressure. The crude product was purified via preparative HPLC to give4-methyl-2-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetamido)thiophene-3-carboxamide.Method [7], MS(ESI) 416.2 [M+H], Retention time=2.254 min.

1.31.4.N-(4-Methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetamide

This compound was prepared from-methyl-2-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)-acetamido)thiophene-3-carboxamideusing Protocol C. The crude product was purified via preparative HPLC togiveN-(4-methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetamide.Method [7], MS(ESI) 440.2 [M+H], Retention time=2.865 min. ¹H-NMR (300MHz, CDCl₃): δ 11.64 (s, 1H), 7.96 (s, 1H), 7.31 (s, 1H), 7.29-7.20 (m,1H), 6.91 (d, J=8.2 Hz, 2H), 6.50 (s, 1H), 4.16-4.12 (m, 2H), 3.81 (s,2H), 3.69-3.65 (m, 2H), 3.42-3.11 (m, 3H), 2.78-2.60 (m, 2H), 2.43 (s,3H), 2.33-2.19 (m, 2H), 2.09-1.91 (m, 4H), 1.50-1.42 (m, 1H).

1.32. Synthesis ofN-(4-methyl-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetamide(32)

This compound was prepared from4-methyl-2-(2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetamido)thiophene-3-carboxamide(Example 1.31.3) using Protocol D. Method [7], MS(ESI) 454.2 [M+H],Retention time=2.857 min. ¹H-NMR (300 MHz, CDCl₃): δ 11.35 (s, 1H),7.28-6.92 (m, 2H), 6.87 (d, J=8.8 Hz, 1H), 6.50 (s, 1H), 4.11-4.08 (m,2H), 3.78 (s, 2H), 3.72-3.68 (m, 2H), 3.35-3.20 (m, 2H), 2.75-2.61 (m,2H), 2.45 (s, 6H), 2.30-2.21 (m, 2H), 2.02-1.91 (m, 5H), 1.50-1.42 (m,1H).

1.33. Synthesis of2-(4-(2-(1H-Imidazol-1-yl)ethoxy)phenyl)-N-(4-methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)acetamide(33)

1.33.1. Methyl 2-(4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)acetate

To a stirring mixture of the methyl 2-(4-hydroxyphenyl)acetate (1.4 g, 1EQ) and 2-(1H-imidazol-1-yl)ethanol (1.0 g) in THF (0.5 mL, 0.5 M) at 0°C. was added PPh₃ (2.9 g). To this mixture was added dropwise DIAD (2.2mL) over 10 min. The reaction mixture was warmed to ambient temperatureovernight. A normal aqueous workup with water and EtOAc was followed.The organic layers were dried over MgSO₄, filtered, and concentratedunder reduced pressure. The crude product was purified via silica gelchromatography to give methyl2-(4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)acetate. Method [1], MS(ESI)261.1, Retention time=0.782 min.

1.33.2. 2-(4-(2-(1H-Imidazol-1-yl)ethoxy)phenyl)acetic acid

To a stirring mixture of 2-(4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)acetate(240 mg) in THF/water (3.3 mL, 10:1) was added fine powder KOH (77 mg).The reaction mixture was stirred at rt overnight. The crude productmixture was acidified with 1.0 N HCl and diluted with EtOAc. A normalaqueous workup with EtOAc was followed. The organic layers were driedover MgSO₄, filtered, and concentrated under reduce pressure. The crudeacid was taken directly to the next reaction without furtherpurification. Method [1], MS(ESI) 247.1, Retention time=0.323 min.

1.33.3.2-(2-(4-(2-(1H-Imidazol-1-yl)ethoxy)phenyl)acetamido)-4-methylthiophene-3-carboxamide

This compound was prepared from2-(4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)acetic acid and2-amino-4-methylthiophene-3-carboxamide using protocol B except thattriethylamine was also added. The crude product was purified via silicagel column chromatography. Method [1], MS(ESI) 385.1, Retentiontime=1.254 min.

1.33.4.2-(4-(2-(1H-Imidazol-1-yl)ethoxy)phenyl)-N-(4-methyl-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)acetamide

The title compound was prepared from2-(2-(4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)acetamido)-4-methylthiophene-3-carboxamideusing protocol C. Method [7], MS(ESI) 409.1 [M+H], Retention time=2.352min; ¹H-NMR (300 MHz, CD₃OD): δ 9.08 (s, 1H), 8.24 (b s, 1H), 7.79 (5,J=1.65 Hz, 1H), 7.62 (5, J=1.65 Hz, 1H), 7.36-7.33 (m, 2H) 7.02-7.0 (m,2H), 6.62 (s, 1H), 4.72 (t, J=4.94 Hz, 2H), 4.45-4.42 (m, 2H), 3.80 (s,2H), 2.48 (s, 3H).

1.34. Synthesis ofN-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(isoquinolin-5-yl)acetamide(34)

1.34.1. Methyl 2-amino-4-bromothiophene-3-carboxylate

Methyl2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-bromothiophene-3-carboxylate(1 g) was stirred in DCM/morpholine (12 mL, 1:1) at rt until all theester was consumed. The crude mixture was concentrated under reducedpressure. The residue was dissolved in ethyl ether. The white solid wasremoved. The mother liquid was concentrated under reduced pressure and a1:1 mixture of ethyl ether/pentane (20 mL) was added. An additionalwhite solid was removed. The organic layer was concentrated underreduced pressure and the crude mixture was placed under high vacuum toremove the excess of morpholine. The crude amine was taken directly tothe next reaction step without further purification. Method [1], MS(ESI)235.9 [M+H], Retention time=1.919 min.

1.34.2. Methyl4-bromo-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate

This compound was prepared from methyl2-amino-4-bromothiophene-3-carboxylate and 2-(isoquinolin-5-yl)aceticacid using protocol A. Method [1], MS(ESI) 404.9 [M+H], Retentiontime=1.678 min.

1.34.3. 4-Bromo-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxamide

The title compound was prepared from methyl4-bromo-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate usingprotocol H. The crude product was purified by preparative HPLC. Method[1], MS(ESI) 389.9, Retention time=1.166 min.

1.34.4N-(4-Bromo-3-(1H)-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(isoquinolin-5-yl)acetamide

The title compound was prepared from4-bromo-2-(2-isoquinolin-5-yl)acetamido)thiophene-3-carboxamide (28 mg)using protocol C and was purified by preparative HPLC. Method [7],MS(ESI) 413.9 [M+H], Retention time=1.50 min. ¹H-NMR (300 MHz, CD₃OD): δ9.72 (b s, 1H), 8.60 (b s, 1H), 8.48 (d, J=7.7 Hz, 2H), 8.24 (d, J=6.6Hz, 2H), 8.09-8.04 (m, 1H), 7.11 (s, 1H), 4.55 (s, 2H).

1.35. Synthesis ofN-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamide(35)

1.35.1. Methyl4-bromo-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxylate

This compound was prepared from methyl2-amino-4-bromothiophene-3-carboxylate and 2-(quinolin-5-yl)acetic acidusing protocol A. Method [1], MS(ESI) 405.0 [M+H], Retention time=1.650min.

1.35.2. 4-Bromo-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxamide

This compound was synthesized from methyl4-bromo-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxylate usingprotocol H. Method [1], MS(ESI) 390.0 [M+H], Retention time=1.174 min.

1.35.3.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamide

This analog was made from4-bromo-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxamide usingprotocol C. The crude product was purified via prep. HPLC to giveN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamide.Method [9], MS{ESI} 413.9 [M+H], Retention time=9.42 min; ¹H-NMR (300MHz, CD₃OD): δ 9.15-9.14 (m, 1H), 9.12 (s, 1H), 8.25-8.21 (m, 2H),8.16-8.10 (m, 1H), 8.0-7.97 (m, 1H), 7.96-7.94 (m, 1H), 7.10 (s, 1H),4.56 (s, 2H).

1.36. Synthesis ofN-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide(36)

1.36.1.4-Bromo-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxamide

This compound was prepared from methyl4-bromo-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxylateusing protocol H. Method [1], MS(ESI) 407.9 [M+H], Retention time=2.043min.

1.36.2.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide

This analog was synthesized from4-bromo-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxamideusing protocol C. Method[7], MS(ESI) 432.0 [M+H], Retention time 4.311min; ¹H-NMR (300 MHz, CD₃Cl) δ 7.89 (bs, 1H), 7.30 -7.20 (m, 3H), 7.097.04 (m, 1H), 6.95 6.93 (m, 2H), 4.92 (s, 2H), 3.11-3.07 (m, 2H),2.93-2.88 (m, 2H),

1.37. Synthesis ofB-(4-Cyano-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(isoquinolin-5-yl)acetamide(37)

1.37.1. Methyl4-cyano-2-(2-(isoquinolin-5-yl)acetamide)thiophene-3-carboxylate

Protocol Y:

To a stirring mixture of methyl4-bromo-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate (100mg) in DMF (0.5 mL) was added CuCN (150 mg). The resulting mixture washeated to 100° C. overnight. The reaction mixture was cooled to roomtemperature. To this mixture was added a 10% NH₄OH solution and ethylether. The crude mixture was stirred at rt for 1 h. A normal aqueousworkup with ethyl ether was followed. The organic layers were dried overMgSO₄, filtered and concentrated under reduce pressure. The crudeproduct mixture was purified by silica gel column chromatography to givemethyl 4-cyano-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate.Method [1], MS(ESI) 352.0 [M+H], Retention time=1.343 min.

1.37.2. 4-Cyano-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxamide

This compound was prepared from methyl4-cyano-2-(2-(isoquinolin-5-yl)acetamido)-thiophene-3-carboxylate usingprotocol H. Method[1], MS(ESI) 337.0 [M+H], Retention time =0.673 min.

1.37.3.N-(4-Cyano-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(isoquinolin-5-yl)acetamide

The title compound was prepared from4-cyano-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxamide (15 mg)according to protocol C except that DCM was added to the DMF-DMA stepand refluxed while the hydrazine step was heated at 90° C. (rather than95° C.). The product was purified via prep. HPLC to giveN-(4-cyano-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(isoquinolin-5-yl)acetamide.Method [7], MS(ESI) 361.1 [M+H], rt=1.273 min; ¹H-NMR (300 MHz, CD₃OD) δ9.62 (b s, 1H), 8.60-8.57 (m, 1H), 8.44-8.37 (m, 2H), 8.34 (s, 1 H),8.29-8.20 (m, 1H), 8.04-8.0 (m, 1H), 7.86 (s, 1H), 4.56 (s, 2H).

1.38. Synthesis ofN-(4-Cyano-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide(38)

1.38.1. Methyl4-cyano-2-(2(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxylate

This compound was prepared from methyl4-bromo-2-(2-(2-oxo-3,4-dihydroquinolin(2H)-yl)acetamido)thiophene-3-carboxylateusing protocol Y. Method[1], MS(ESI) 370.0 [M+H], Retention time=2.237min.

1.38.2.4-Cyano-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxamide

This compound was prepared from methyl4-cyano-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxylateusing protocol H. Method[1], MS(ESI) 355.0 [M+H], Retention time=3.392min.

1.38.3.N-(4-Cyano-3-(1H-1,2,4-triazol-5-yl)thiophen-2yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide

This analog was synthesized from4-cyano-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxamideusing protocol C. The crude product was purified via preparative HPLC togiveN-(4-cyano-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide.Method[7], MS(ESI) 379.1 [M+H], Retention time=3.91 min; ¹H-NMR (300MHz, CDCl₃) δ 12.34 (s, 1 H), 8.13 (s, 1H), 7.62 (s, 1H), 7.28 7.10 (m,2H), 7.06-7.01 (m, 1H), 6.94 (d, J=7.7 Hz, 1H), 4.92 (s, 2H), 3.12-3.06(m, 2H), 2.91-2.86 (m, 2H).

1.39. Synthesis ofN-(2-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(4-(2-oxopyrrolidin-1-yl)phenyl)acetamide(39)

1.39.1. 3-(2-(4-iodophenyl)acetamido)thiophene-2-carboxamide

This compound was prepared from 2-(4-iodophenyl)acetic acid and3-aminothiophene-2-carboxamide using protocol B. Method [1], MS(ESI)387.0 [M+H], Retention time=1.777 min.

1.39.2.3-(2-(4-(2-Oxopyrrolidin-1yl)phenyl)acetamido)thiophene-2-carboxamide

To a stirring mixture of3-(2-(4-iodophenyl)acetamido)thiophene-2-carboxamide (300 mg) in dioxane(2 mL) at rt was added CuI (103 mg), K₂CO₃ (325 mg), pyrrolidin-2-one(80 mg), and rac-dimethylcyclohexane-1,2-diamine (92 mg). The resultingmixture was heated to 90° C. overnight. The crude product mixture wasdiluted with saturated NaHCO₃ solution and extracted with EtOAc. Theorganic layers were dried over MgSO₄, filtered, and concentrated underreduced pressure. The product was purified via silica gel chromatographyto give2-(2-(4-(2-oxopyrrolidin-1yl)phenyl)acetamido)thiophene-3-carboxamide.Method[1], MS(ESI) 344.1, Retention time=1.476 min.

1.39.3.N-(2-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-3-yl)-2-(4-(2-oxopyrrolidin-1-yl)phenyl)acetamide

This analog was prepared from3-(2-(4-(2-oxopyrrolidin-1-yl)phenyl)-acetamido)thiophene-2-carboxamideusing protocol C. Method[7], MS(EST) 382.1 [M+H], Retention time=3.46min; ¹H-NMR (300 MHz, CDCl₃) δ 10.02 (s, 1H), 8.13 (d, J=5.5 Hz, 1H),7.46-7.38 (m, 4H), 7.30 (d, J=5.5 Hz, 1H), 3.97-3.93 (m, 2H), 3.87 (s,2H), 2.78-2.72 (m, 2H), 2.52 (s, 3H), 2.40- 2.25 (m, 2H),

1.40. Synthesis ofN-(4-methyl-3-(5-methyl-4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(4-(pyridin-4-yl)phenyl)acetamide(40)

1.40.1. 2-(2-(4-Iodophenyl)acetamido)-4-methylthiophene-3-carboxamide

To a solution of 2-amino-4-methylthiophene-3-carboxamide (1 g, 6.4 mmol)and 2-(4-iodophenyl)acetic acid (1.83 g, 7.0 mmol) in methylene chloride(10 mL) was added Hunig's base (i.e., N,N-diisopropylethylamine) (3.1mL, 18 mmol) and HATU (2.66 g, 7.0 mmol). The heterogeneous mixture wasstirred for 18 h. The reaction was quenched by addition of saturatedaqueous ammonium chloride solution and the biphasic mixture wasextracted with additional methylene chloride. The organic layer waswashed with brine, dried over sodium sulfate and concentrated underreduced pressure to provide a pale brown solid. LCMS Method [2]: rt=2.02min; M+Na 423.0 Material was used without further purification.

1.40.2.2-(4-Iodophenyl)-N-(4-methyl-3-(5-methyl-4H-1,2,4-triazol-3-yl)thiophen-2-yl)acetamide

The title compound was prepared from2-(2-(4-iodophenyl)acetamido)-4-methylthiophene-3-carboxamide (277 mg,0.69 mmol) using protocol D and was purified by column chromatographyusing 3% MeOH/methylene chloride (140 mg, 46% yield). Method [1]:rt=2.11 min; MH+ 438.9.

1.40.3.N-(4-Methyl-3-(5-methyl-4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(4-(pyridin-4-yl)phenyl)acetamide

A 30 mL reaction vial was charged with2-(4-iodophenyl)-N-(4-methyl-3-(5-methyl-4H-1,2,4-triazol-3-yl)thiophen-2-yl)acetamide(140 mg, 0.32 mmol), pyridin-4-ylboronic acid (60 mg, 0.48 mmol), sodiumbicarbonate (100 mg, 1.2 mmol). DME (2 mL), and water (2 mL). Theheterogeneous mixture was stirred vigorously under a stream of nitrogenfor 5 minutes before Pd(PPh₃)₄ was added and the vial was sealed underits Teflon cap. The reaction mixture was heated to 90° C. for 3.25 hbefore being transferred to a microwave vial and being microwaved to150° C. for 5 minutes. The reaction mix was concentrated under reducedpressure and the residue was partitioned between methylene chloride anda saturated aqueous solution of ammonium chloride. The organic solutionwas washed with brine and dried over sodium sulfate. The solution wasconcentrated under reduced pressure and the crude product was purifiedby column chromatography (3.5% MeOH/methylene chloride) Yield: 10.0 mg(8%). Method [1]: rt=1.136 min; MH+ 390.2. ¹H-NMR (300 MHz, CD₃OD) δ8.71 (d, J=6.3 Hz, 1H), 8.60 (dd, J=4.6, 1.6 Hz, 2H), 7.84 (d, J=8.0 Hz,2H), 7.77 (dd, J=4.6, 1.6 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H), 6.58 (s, 1H),3.94 (s, 2H), 2.45 (s, 3H), 2.31 (s, 3H).

1.41. Synthesis ofN-(4-cyano-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamide(41)

1.41.1. Methyl4-bromo-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxylate

The title compound was prepared from methyl2-amino-4-bromothiophene-3-carboxylate (660 mg, 2.8 mmol) and2-(quinolin-5-yl)acetic acid using protocol A. 560 mg (49% yield).Method [1]: rt=1.666 min; MH+ 405/407.

1.41.2. Methyl4-cyano-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxylate

A 20 mL microwave vessel was charged with methyl4-bromo-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxylate (560 mg,1.38 mmol), CuCN (540 mg, 6 mmol), DMF (8 mL), and(1R,2R)-N¹,N²-dimethylcyclohexane-1,2-diamine (300 uL). The reactionmixture was flushed with nitrogen and sealed under a teflon cap beforebeing heated to 150° C. using microwave radiation for 0.5 h. Thereaction mixture was concentrated under reduced pressure to give an oilthat was partitioned between an organic layer of 10% iPrOH/chloroformand an aqueous layer saturated with sodium bicarbonate. Theheterogeneous organic layer was filtered and concentrated under reducedpressure to give a green oil. The crude product was purified by columnchromatography with 60-70% ethyl acetate/hexanes. 40 mg (8%). Method[1]: rt=1.401 min; MH+ 352.0.

1.41.3. 4-Cyano-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxamide

The title compound was prepared from methyl4-cyano-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxylate usingprotocol H (8 mg, 80% yield). Method [1]: rt=0.665 min; MH+ 337.0.

1.41.4.(Z)-4-Cyano-N-((dimethylamino)methylene)-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxamide

The title compound was prepared from4-cyano-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxamide (37 mg,0.11 mmol) according to protocol C and was used without furtherpurification. Method [1]: rt=1.291 min, MH+ 392.1.

1.41.5.N-(4-Cyano-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamide

To a mixture of4-cyano-N-((dimethylamino)methylene)-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxamide(0.11 mmol) in HOAc (2 mL) was added hydrazine. (19 uL of 65% aqueoussolution). The reaction mixture was heated to 87° C. for 12 hours andwas then cooled to 23° C. and concentrated. The residue was taken up ina 10% isopropanol/chloroform solution and washed with a saturated,aqueous solution of sodium bicarbonate. The organic solution was driedover sodium sulfate and concentrated to give a solid, which was purifiedby column chromatography (using 5 to 10% methanol/methylene chloride)and prep-HPLC (5-40% MeCN gradient). 5 mgs (13% for the final 2 steps).Method [8]: rt=8.1 min; MH+ 361.1. ¹H-NMR (300 MHz, CDCl₃) δ 8.86 (s,1H), 8.48 (d, J=8.6 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.85 (m, 2H), 7.69(d, J=6.6 Hz, 1H), 7.54 (m, 2H), 4.34 (s, 2H), 3.30 (s, 3H). ¹³C-NMR (75MHz, DMSO-d₆) δ 168.7, 158.9, 158.4, 149.5, 139.5, 132.3, 131.3, 131.2,130.5, 127.9, 127.2, 122.3, 118.3, 115.7, 112.5, 105.7, 105.6.

Compounds of Examples 1.42 through 1.48, below, were synthesized byactivation of the corresponding carboxylic acids and condensation with4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine, which was preparedaccording to the scheme, below.

1.42.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-7-(trifluoromethyl)quinolin-1(2H)-yl)-acetamide

Retention time (min)=5.456, method [7], MS(ESI) 497.9 (M+H); ¹H NMR (300MHz, CD₃OD) δ 7.92 (d, J=9.8 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.73 (s,1H), 7.52-7.55 (m, 2H), 6.96-7.01 (m, 2H), 5.34 (s, 2H).

1.43.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide

Method [7], MS(ESI) 450.0 [M+H], Retention time=4.428 min. ¹H-NMR (300MHz, CDCl₃) δ 7.80 (s, 1H), 7.28 (s, 1H), 7.10-7.0 (m, 2H), 6.94 (s,1H), 4.86 (d, J=3.84 Hz, 2H), 3.12-3.06 (m, 2H), 2.86-2.81 (m, 2H).

1.44.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7-fluoro-2-oxoquinolin-1(2H)-yl)acetamide

Method [7], MS(ESI) 448.0 [M+H], Retention time=4.417 min; ¹NMR (300MHz, CDCl₃) δ 7.86 (d, J=8.9 Hz, 1H), 7.70 (s, 1H), 7.66-7.60 (m, 1H)7.04-6.90 (m, 2H), 6.95 (s, 1H), 6.85 (d, J=9.34 Hz, 1H), 5.26 (s, 2H).

1.45.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide

Method [7], MS(ESI) 466.0 [M+H], Retention time==5.594 min; ¹H-NMR (300MHz, CDCl₃) δ 7.93 (s, 1H), 7.17 (d, J=7.7 Hz, 1H), 7.04 (dd, J=8.24,1.65 Hz, 1H), 6.98 (s, 1H), 6.94 (d, J=1.65 Hz, 1H), 4.88 (s, 2H),3.08-3.03 (m, 2H), 2.93-2.85 (m, 2H).

1.46.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6,7-difluoro-2-oxoquinolin-1(2H)-yl)acetamide

Method [7], MS(ESI) 465.9 [M+H], Retention time=4.516 min; ¹H-NMR (300MHz, CDCl₃) δ 8.58 (b s, 1H), 8.07 (d, J==9.8 Hz, 1H), 8.02 (dd,J=10.44, 8.8 Hz, 1H), 7.91-7.84 (m, 1H), 7.33 (s, 1H), 6.79 (d, J=9.9Hz, 1H), 5.27 (s, 2H).

1.47.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

Method [7], MS(ESI) 497.9 [M+H], Retention time=5.696 min. ¹H-NMR (300MHz, CDCl₃) δ 12.87 (b s, 1H), 7.92 (d, J=6.6 Hz, 1H), 7.73 (s, 1H),7.77 (d, J=8.24 Hz, 1H), 7.73 (s, 1H), 7.42 (d, J=9.34 Hz, 1H), 6.98 (d,J=9.9 Hz, 1H), 6.95 (s, 1H), 5.33 (s, 2H).

1.48.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoro-2-oxaquinolin-1(2H)-yl)acetamide

Method[7], MS(ESI) 448.0 [M+H], Retention time=4.347 min; ¹-NMR (300MHz, CDCl₃) δ 7.82 (d, J=9.9 Hz, 1H), 7.68 (s, 1H), 7.37-7.33 (m, 1H),7.28 (s, 1H), 7.26-7.23 (m, 1H), 6.95-6.92 (m, 2H), 5.30 (s, 2H).

1.49. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)(thiophen-2-yl)-2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetamide

1.49.1 Methyl 2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetate

The title compound was prepared from 1,6-naphthyridin-2(1H)-oneaccording to protocol K. Retention time (min)=0.949, method [3], MS(ESI)219.1 (M+H).

1.49.2. 2-(2-Oxo-1,6-naphthyridin-1(2H)-yl)acetic acid

To a solution of methyl 2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetate (1.51g, 6.92 mmol) in THF (10 mL) was added sodium hydroxide (4 mL of a 3 Naqueous solution, 13.8 mmol) and the reaction mixture was stirred atroom temperature for 18 h. The resulting solution was diluted with ethylacetate and washed with water. The aqueous phase was separated, adjustedto pH 2 with aqueous HCl and extracted with ethyl acetate. The organicphase was separated, dried (Na₂SO₄), filtered and concentrated undervacuum to give 2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetic acid. Retentiontime (min)=0.368, method [3], MS(ESI) 205.0 (M+H).

1.49.3.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetic acid (62 mg, 0.306 mmol) and4-bromo-3-(1H)-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.101 mmol)according to Protocol L. Retention time (min)=1.258, method [7], MS(ESI)431.0 (M+H); ¹H NMR (300 MHz, CD₃OD) δ 9.10 (s, 1H), 8.65 (d, J=6.5 Hz,1H), 8.33 (s, 1H), 8.23 (d, J=9.7 Hz, 1H), 7.75 (d, J=6.5 Hz, 1H), 7.15(s, 1H), 7.01 (d, J=9.7 Hz, 1H), 5.39 (s, 2H).

1.50. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetamide

1.50.1. Methyl 2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetate

1,5-naphthyridin-2(1H)-one (2.05 g, 14.0 mmol) was treated with lithiumhexamethyldisilazide instead of sodium hydride according to protocol Kto give methyl 2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetate (224 mg).Retention time (min)=2.084, method [3], MS(ESI) 219.0 (M+H).

1.50.2. 2-(2-Oxo-1,5-naphthyridin-1(2H)-yl)acetic acid

To a solution of methyl 2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetate(0.205 g, 0.939 mmol) in THF (5 mL) was added sodium hydroxide (0.939 mLof a 3 N aqueous solution, 2.818 mmol) and the reaction mixture wasstirred at 70° C. for 0.5 h. The resulting solution was concentratedunder vacuum and co-evaporated from toluene to give2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetic acid. Retention time(min)=1.033, method [3], MS(ESI) 205.1 (M+H).

1.50.3.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetic acid (42 mg, 0.204 mmol) and4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.101 mmol)according to protocol A. Retention time (min)=2.295, method [7], MS(ESI)431.0 (M+H); ¹NMR (300 MHz, CD₃OD): δ 8.57 (dd, J=4.6, 1.7 Hz, 1H), 8.16(d, J=9.9 hz, 1H), 8.11 (s, 1H), 7.98 (d, J=9.1 Hz, 1H), 7.62 (dd,J=8.8, 5.1 Hz, 1H), 7.01 (d, J=4.3 Hz, 1H), 7.05 (s, 1H), 5.33 (s, 2H).

1.51 Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetamide

1.51.1. 2-(2-Oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetic acid

A suspension of 2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetic acid (150 mg,0.734 mmol) and Pd/C (20 mg) in methanol was shaken under a 40 psiatmosphere of H₂ for 18 h. The suspension was filtered through Celiteand the filtrate was concentrated under vacuum to give2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetic acid. Retentiontime (min)=0.343, method [3], MS(ESI) 207.1 (M+H).

1.51.2.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetic acid (40 mg, 0.195mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (24 mg,0.0979 mmol) according to protocol A. Retention time (min)=8.108, method[6], MS(ESI) 433.0 (M+H); ¹H NMR (300 MHz, CD₃OD): δ 8.61-8.48 (m, 3H),7.51 (d, J=6.8 Hz, 1H), 7.16 (s, 1H), 5.08 (s, 2H) 3.29-3.25 (m, 2H),2.98-2.93 (m, 2H).

1.52. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

1.52.1. 2(2-Oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid

2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetic acid (90 mg, 0.441 mmol) wastreated according to Example 1.51.1 to give2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid. Retentiontime (min)=0.262,method [3], MS(ESI) 207.0 (M+).

1.52.2.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

N-(4-Bromo-3-(1H-1,2,4-triazole-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamidewas prepared from 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)aceticacid (42 mg, 0.203 mmol) and4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.102 mmol)according to protocol A. Retention time (min)=1.274, method [7], MS(ESI)433.0 (M+H); ¹H NMR (300 MHz, CD₃OD): δ 8.35 (s, 1H), 8.23 (d, J=4.5 Hz,1H), 7.65 (d, J=9.2 Hz, 1H), 7.45 (dd, J=9.2, 4.5 Hz, 1H), 7.12 (s, 1H),4.91 (s, 2H) 3.34-3.33 (m, 2H), 2.98-2.93 (m, 2H).

1.53. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)acetamide

1.53.1 Ethyl 3-(2-amino-4-(trifluoromethoxy)phenyl)acrylate

The title compound was prepared from 2-bromo-5-(trifluoromethoxy)anilineaccording to protocol M. Retention time (min)=2.693, method [1], MS(ESI)276.1 (M+H).

1.53.2. 7-(Trifluoromethoxy)quinolin-2(1H)-one

7-(Trifluoromethoxy)quinolin-2(1H)-one was prepared from ethyl3-(2-amino-4-(trifluoromethoxy)phenyl)acrylate according to protocol N.Retention time (min)=1.803, method [1], MS(ESI) 230.1 (M+H).

1.53.3. Methyl 2-(2-oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)acetate

The title compound was prepared from7-(trifluoromethoxy)quinolin-2(1H)-one according to protocol K.Retention time (min)=2.226, method [1], MS(ESI) 302.0 (M+H).

1.53.4. 2-(2-Oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid

Methyl 2-(2-oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)acetate (0.49 g,1.62 mmol) was dissolved in THF (4 mL). Sodium hydroxide (1.08 mL of a 3N aqueous solution, 3.25 mmol) was added and the reaction mixture wasstirred 60° C. for 2 h. The resulting solution was diluted with ethylacetate and washed with water. The aqueous phase was separated, adjustedto pH 2 with aqueous HCl and extracted with ethyl acetate. The organicphase was separated, dried (Na₂SO₄), filtered and concentrated undervacuum to give 2-(2-oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)aceticacid. Retention time (min) 1.75, method [1], MS(ESI) 288.1 (M+H).

1.53.5.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-oxo-7-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid (79 mg, 0.275mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (35 mg,0.137 mmol) according to protocol A. Retention time (min)=6.037, method[7], MS(ESI) 514.0 (M+H); ¹H NMR (300 MHz, CD₃OD): δ 8.15 (s, 1H), 8.11(d, J=9.9 Hz, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.41 (s, 1H), 7.26 (m, 1H),7.10 (s, 1H), 6.81 (d, J=9.9 hz, 1H), 5.31 (s, 2H).

1.54 Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetamide

1.54.1. Methyl 2-(7-bromo-2-oxoquinolin-1(2H)-yl)acetate

The title compound was prepared from 7 bromoquinolin-2(1H)-one accordingto protocol K. Retention time (min)=1.89, method [1], MS(ESI) 296.0(M+H).

1.54.2. Methyl 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetate

CuCN (0.211 g, 2.36 mmol) and Pd(PPh₃)₄ (0.136 g, 0.118 mmol) were addedto a solution of methyl 2-(7-bromo-2-oxoquinolin-1(2H)-yl)acetate (0.35g, 1.18 mmol) in DMF (1 mL) in a screw cap vial. The vial was sealed andplaced into a oil bath at 120° C. and the reaction mixture was stirredfor 18 h. The resulting mixture was diluted with Et₂O and washed withbrine. The organic phase was separated, dried (Na₂SO₄), filtered,concentrated under vacuum and the residue was purified on a silica gelcolumn to give methyl 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetate (0.204g, 71%). Retention time (min)=1.464, method [1], MS(ESI) 243.1 (M+H).

1.54.3. 2-(7-Cyano-2-oxoquinolin-1(2H)-yl)acetic acid

Trimethyl tin hydroxide (0.388 g, 2.14 mmol) was added to a solution ofmethyl 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetate (0.104 g, 0.429 mmol)in 1,2-dichloroethane (5 mL) and the resulting suspension was stirred atreflux for 4 h. The reaction mixture was diluted with dichloromethaneand washed with 1N aqueous HCl. Filtration of the organic phase provided87 mg (89%) of 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetic acid. Retentiontime (min)=0.987, methanol [1], MS(ESI) 229.1 (M+H).

1.54.4.(N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetamide

N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetamidewas prepared from 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetic acid (65 mg,0.286 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (21mg, 0.143 mmol) according to protocol A. Retention time (min)=4.143,method [7], MS(ESI) 454.9 (M+H); ¹H NMR (300 MHz, DMSO-d₆): δ 12.18 (s,1H), 8.56 (s, 1H), 8.24 (s, 1H), 8.16 (d, J=9.0 Hz, 1H), 8.01 (d, J=8.0Hz, 1H), 7.70 (d, J=8.01 Hz, 1H), 7.28 (s, 1H), 6.90 (d, J=9.0 Hz, 1H),5.31 (s, 2H).

1.55. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(isoquinolin-8-yl)acetamide

N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(isoquinolin-8-yl)acetamidewas prepared from 2-(isoquinolin-8-yl)acetic acid (53 mg, 0.286 mmol)and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (35 mg, 0.143mmol) according to protocol A. Retention time (min)=1.769, method [7],MS(ESI) 414.0 (M+H); ¹H NMR (300 MHz, CD₃OD): δ 9.84 (bs, 1H), 8.55 (bs,1H), 8.41 (d, J=6.0 Hz, 1H), 8.26-8.23 (m, 2H), 8.18 (dd, J=8.1, 7.2 Hz,1H), 7.99 (d, J=4.0 Hz, 1H), 7.09 (s, 1H), 4.61 (s, 2H).

1.56. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroquinolin-5-yl)acetamide

N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroquinolin-5-yl)acetamidewas prepared from 2-(6-fluoroquinolin-5-yl)acetic acid (42 mg, 0.203mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg,0.102 mmol) according to protocol A. Retention time (min)=2.499, method[7], MS(ESI) 432.0 (M+H); ¹H NMR (300 MHz, CD₃OD): δ 8.99 (dd, J=4.2,1.1 Hz, 1H), 8.86 (d, J=7.9 Hz, 1H), 8.23 (dd, J=8.9, 4.5 Hz, 1H), 8.08(s, 1H), 7.85 (dd, J=9.4, 9.2 Hz, 1H), 7.81 (dd, J=9.2, 4.5 Hz, 1H),7.07 (s, 1H), 4.48 (s, 2H).

1.57 Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroquinolin-7-yl)acetamide

N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroquinolin-7-yl)acetamidewas prepared from 2-(6-fluoroquinolin-7-yl)acetic acid (42 mg, 0.203mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg,0.102 mmol) according to protocol A. Retention time (min)=2.338, method[7], MS(ESI) 432.0 (M+H); ¹H NMR (300 MHz, CD₃OD): δ 9.02 (d, J=4.2 Hz,1H), 8.73 (d, J=8.0 Hz, 1H), 8.24 (d, J=7.2 Hz, 1H), 7.93 (s, 1H), 7.88(d, J=10.0 Hz, 1H), 7.82 (dd, J=9.0, 4.2 Hz, 1H), 7.09 (s, 1H), 4.42 (s,2H).

1.58. Synthesis ofN-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-7-(trifluoromethyl)-1,6-naphthyridin-1(2H)-yl)acetamide

1.58.1. 5-Iodo-2-(trifluoromethyl)pyridin-4-ol

Iodine (8.16 g, 32.1 mmol) was added in five portions to a solution of2-(trifluoromethyl)pyridin-4-ol (5 g, 30.65 mmol) and K₂CO₃ (4.66 g,33.7 mmol) in methanol (34 mL) at 0° C. and the resulting mixture wasstirred at room temperature for 20 h. The solution was washed withsaturated aqueous sodium sulfite then acetic acid (10 mL) was added andthe solution was extracted with ethyl acetate, dried (Na₂SO₄), filtered,concentrated under vacuum and the residue was purified on a silica gelcolumn to give 5-iodo-2-(trifluoromethyl)pyridin-4-ol (5.1 g, 57%).Retention time (min)=1.761, method [1], MS(ESI) 290.9 (M+H).

1.58.2. 4-Chloro-5-iodo-2-(trifluoromethyl)pyridine

A solution of 5-iodo-2-(trifluoromethyl)pyridin-4-ol (4.8 g, 16.6 mmol)in POCl₃ (30 mL) was heated to 100° C. for 30 minutes. The resultingsolution was concentrated under vacuum and the residue was neutralizedby the addition of ice and aqueous potassium carbonate. The solution wasextracted with ethyl acetate, dried (Na₂SO₄), filtered and concentratedunder vacuum to give 4-chloro-5-iodo-2-(trifluoromethyl)pyridine.Retention time (min)=2.594, method [1], MS(ESI) 307.9 (M+H).

1.58.3. 5-Iodo-2-(trifluoromethyl)pyridin-4-amine

Concentrated aqueous ammonium hydroxide (10 mL) was added to a solutionof 4-chloro-5-iodo-2-(trifluoromethyl)pyridine (4.11 g, 13.3 mmol) inDMSO in a glass pressure tube. The tube was sealed and placed in an oilbath pre-heated to 110° C. for 48 h. The resulting solution was dilutedwith brine, extracted with ethyl acetate, dried (Na₂SO₄), filtered andconcentrated under vacuum to give5-iodo-2-(trifluoromethyl)pyridin-4-amine. Retention time (min)=1.584,method [1], MS(ESI) 289.0 (M+H).

1.58.4. Ethyl 3-(4-amino-6-(trifluoromethyl)pyridin-3-yl)acrylate

Ethyl 3-(4-amino-6-(trifluoromethyl)pyridin-3-yl)acrylate was preparedfrom 5-iodo-2-(trifluoromethyl)pyridin-4-amine according to protocol M.Retention time (min)=1.064, method [1], MS(ESI) 215.1 (M+H).

158.5 7-(Trifluoromethyl)-1,6-naphthyridin-2(1H)-one

7-(Trifluoromethyl)-1,6-naphthyridin-2(1H)-one was prepared from ethyl3-(4-amino-6-(trifluoromethyl)pyridine-3-yl)acrylate according toprotocol N. Retention time (min)=1.064, method[1], MS(ESI) 215.1 (M+H).

1.58.6. Methyl2-(2-oxo-7-(trifluoromethyl)-1,6-naphthyridin-1(2H)-yl)acetate

Methyl 2-(2-oxo-7-(trifluoromethyl)-1,6-naphthyridin-1(2H)-yl)acetatewas prepared from 7-(trifluoromethyl)-1,6-naphthyridin-2(1H)-oneaccording to Protocol K. Retention time (min)=1.621, method [1], MS(ESI)287.1 (M+H).

1.58.7. 2-(2-oxo-7-(trifluoromethyl)-1,6-naphthyridin-1(2H)-yl)aceticacid

Methyl 2-(2-oxo-7-(trifluoromethyl)-1,6-naphthyridin-1(2H)-yl)acetate(0.069 g, 0.10 mmol) was treated according to Example 1.53.4 to give2-(2-oxo-7-(trifluoromethyl)-1,6-naphthyridin-1(2H)-yl)acetic acid.Retention time (min)=1.081, method [1], MS(ESI) 273.1 (M+H).

1.58.8.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-7-(trifluoromethyl)-1,6-naphthyridin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-oxo-7-(trifluoromethyl)-1,6-naphthyridin-1(2H)-yl)acetic acid (55mg, 0.203 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine(25 mg, 0.102 mmol) according to protocol A. Retention time (min)=4.505,method [7], MS(ESI) 499.0 (M+H); ¹H NMR (300 MHz, CD₃OD): δ 9.06 (s,1H), 8.31 (s, 1H) 8.24 (d, J=9.4 Hz, 1H), 7.94 (s, 1H), 7.14 (s, 1H),6.99 (d, J=9.4 Hz, 1H), 5.39 (s, 2H).

1.59. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamide

1.59.1. Pyrazolo[1,5-a]pyrimidin-5(4H)-one

1,3-Dimethyl uracil (3.15 g, 22.5 mmol) and sodium ethoxide (23 mL of a21% solution in ethanol) were added to a solution of 1H-pyrazol-5-amine(1.7 g, 20.4 mmol) in ethanol (50 mL). The resulting mixture was heatedto 60° C. for 2 h and was then cooled to room temperature. The palebrown solid was isolated by filtration to givepyrazolo[1,5-a]pyrimidin-5(4H)-one (1.6 g, 58%). Retention time(min)=0.820, method [3], MS(ESI) 136.1 (M+H).

1.59.2. Methyl 2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetate

methyl 2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetate was preparedfrom pyrazolo[1,5-a]pyrimidin-5(4H)-one according to Protocol K.Retention time (min)=1.951, method [3], MS(ESI) 208.1 (M+H).

1.59.3. 2-(5-Oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetic acid

Methyl 2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetate (0.26 g, 1.25mmol) was treated according to Example 1.54.3 to give2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetic acid. Retention time(min)=1.00, method [3], MS(ESI) 194.1 (M+H).

1.59.4.N-(4-Bromo-3(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamide

The title compound was prepared from2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetic acid (39 mg, 0.203mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg,0.102 mmol) according to protocol A. Retention time (min)=2.451, method[7], MS(ESI) 420.0 (M+H); ¹H NMR (300 MHz, CDCl₃): δ 8.28 (d, J=8.5 Hz,1H), 7.83 (s, 1H), 7.77 (d, J=2.6 Hz, 1H), 6.97 (s, 1H), 6.25 (d, J=7.9Hz, 1H), 5.94 (d, J=2.6 Hz, 1H), 4.98 (s, 2H).

1.60. Synthesis of2-(2-oxo-1,6-naphthyridin-1(2H)-yl)-N-(2-thiazol-4-yl)thiophen-3-yl)acetamide

The title compound was prepared from2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetic acid (83 mg, 0.307 mmol) and3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (28 mg, 0.154 mmol) accordingto protocol A. Retention time (min)=1.460, method [7], MS(ESI) 369.1(M+H); ¹H NMR (300 MHz, CD₃OD): δ 9.09 (s, 1H), 8.89 (d, J=2.3 Hz, 1H),8.62 (d, J=6.6 Hz, 1H), 8.23 (d, J=9.7 Hz, 1H), 7.81-7.76 (m, 2H), 7.65(d, J=2.3 Hz, 1H), 7.35 (d, J=5.5 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 5.30(s, 2H).

1.61. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetamide

1.61.1. 2-Iodo-6-(trifluoromethyl)pyridin-3-amine

Iodine (7.83 g, 30.84 mmol) and silver sulfate (9.6 g, 30.84 mmol) wereadded to a solution of 6-(trifluoromethyl)pyridin-3-amine (5 g, 30.84mmol) in ethanol (200 ml) and the resulting suspension was stirred atroom temperature for 18 h, the solution was filtered and the filtratewas concentrated under vacuum. The residue was re-dissolved in methylenechloride and washed with aqueous NaOH (1 N), dried (Na₂SO₄), filteredand concentrated under vacuum to give2-iodo-6-(trifluoromethyl)pyridin-3-amine. Retention time (min)=2.136,method [1], MS(ESI) 289.01 (M+H).

1.61.2. Ethyl 3-(3-amino-6-(trifluoromethyl)pyridin-2-yl)acrylate

Ethyl 3-(3-amino-6-(trifluoromethyl)pyridin-2-yl)acrylate was preparedfrom 2-iodo-6-(trifluoromethyl)pyridin-3-amine according to protocol M.Retention time (min)=2.350, method [1], MS(ESI) 261.1 (M+H).

1.61.3. 6-(Trifluoromethyl)-1,5-naphthyridin-2(1H)-one

6-(Trifluoromethyl)-1,5-naphthyridin-2(1H)-one was prepared from ethyl3-(3-amino-6-(trifluoromethyl)pyridin-2-yl)acrylate according toprotocol N. Retention time (min)=1.401, method [1], MS(ESI) 215.0 (M+H).

1.61.4. Methyl2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetate

Methyl 2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetatewas prepared from 6-(trifluoromethyl)-1,5-naphthyridin-2(1H)-oneaccording to Protocol K. Retention time (min)=1.822 method [1], MS(ESI)287.1 (M+H).

1.61.5. 2-(2-Oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)aceticacid

Methyl 2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetate(0.15 g, 0.524 mmol) was treated according to Ex. 1.53.4 to give2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetic acid.Retention time (min)=1.535, method [1], MS(ESI) 273.0 (M+H).

1.61.6.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetic acid (66mg, 0.245 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine(30 mg, 0.122 mmol) according to protocol A. Retention time (min)=5.195,method [7], MS(ESI) 499.0 (M+H); ¹H NMR (300 MHz, CD₃OD): δ 8.26-8.21(m, 3H), 7.96 (d, J=8.9 Hz, 1H), 7.17-7.13 (m, 2H), 5.37 (s, 2H).

1.62. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(5-oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamide

1.62.1. 2-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one

3-(Trifluoromethyl)-1H-pyrazol-5-amine (4.8 g, 31.7 mmol) was subjectedto the protocol in example 1.59.1 to give2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one. Retention time(min)=1.220, method [1], MS(ESI) 204.0 (M+H).

1.62.2. methyl2-(5-oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetate

Methyl2-(5-oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetatewas prepared from 2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5(4H)-oneaccording to protocol K. Retention time (min)=1.846, method [1], MS(ESI)276.0 (M+H).

1.62.3.2-(5-Oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-4(5H)-yl)aceticacid

Methyl2-(5-oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetate(0.129 g, 0.469 mmol) was subjected to the conditions in Example 1.54.3to give2-(5-oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-4(5H)-yl)aceticacid. Retention time (min)=1.448, method [1], MS(ESI) 262.2 (M+H).

1.62.4.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(5-oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamide

The title compound was prepared from2-(5-oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-4(5H)-yl)aceticacid (63 mg, 0.244 mmol) and4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (30 mg, 0.122 mmol)according to protocol A. Retention time (min)=4.975, method [7], MS(ESI)488.0 (M+H); ¹H NMR (300 MHz, DMSO-d₆): δ 8.79 (d, J=7.4 Hz, 1H), 8.61(bs, 1H), 7.32 (s, 1H), 6.96 (s, 1H), 6.45 (d, J=7.4 Hz, 1H), 5.01 (s,2H).

1.63. Synthesis ofN-(4-bromo-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

Sodium hydride (4.2 mg of a 60% dispersion in mineral oil, 0.107 mmol)was added to a solution ofN-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide(31 mg, 0.0715 mmol) in DMF (0.1 mL) at 0° C. The suspension was stirredfor 5 minutes after which iodomethane (12 mg, 0.058 mmol) was added. Thereaction mixture was stirred at room temperature for 20 minutes thendiluted with water, extracted with ethyl acetate, dried (Na₂SO₄)filtered, concentrated under vacuum and purified by preparation HPLC togiveN-(4-bromo-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide.Retention time (min)=1.740, method [7], MS(ESI) 447.0 (M+H); ¹H NMR (300MHz, CD₃OD): δ 8.47 (s, 1H), 8.33 (d, J=5.2 Hz, 1H), 7.85 (bs, 1H), 7.61(bs, 1H), 7.11 (s, 1H), 4.94 (s, 2H), 4.02 (s, 3H), 3.41-3.36 (m, 2H),3.01-2.97 (m, 2H).

1.64. Synthesis ofN-(4-Chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamide

The title compound was prepared from2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetic acid (94 mg, 0.488mmol) and 4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (49 mg,0.244 mmol) according to protocol A. Retention time (min)=2.161, method[7], MS(ESI) 376.0 (M+H); ¹H NMR (300 MHz, CDCl₃): δ 8.31 (d, J=8.1 Hz,1H), 7.83 (s, 1H), 7.76 (s, 1H), 6.85 (s, 1H), 6.27 (d, J=8.1 HZ, 1H),5.94 (s, 1H), 4.98 (s, 2H).

1.65. Synthesis ofN-(4-Chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamide

Iodomethane (36 mg, 0.255 mmol) and K₂CO₃ (44 mg, 0.319 mmol) were addedto a solution ofN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamide(80 mg, 0.212 mmol) in DMF (1 mL). The reaction mixture was stirred atroom temperature for 30 minutes and was subsequently diluted with ethylacetate and washed with brine. The organic phase was dried (Na₂SO₄),filtered, concentrated under vacuum and purified by preparation HPLC togiveN-(4-chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetamide.Retention time (min)=3.00, method [&], MS(ESI) 390.1 (M+H); ¹H NMR (300MHz, CD₃Cl): δ 8.25 (d, J=8.2 Hz, 1H), 7.90 (s, 1H), 7.76 (d, J=2.1 Hz,1H), 6.79 (s, 1H), 6.22 (d, J=8.2 Hz, 1H), 5.97 (d, J=2.1 Hz, 1H), 5.36(s, 2H), 3.99 (s, 3H).

1.66. Synthesis ofN-(4-Chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetamide

The title compound was prepared fromN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetamide(51 mg, 0.112 mmol) using the conditions in Example 1.65, and waspurified by preparative HPLC. Retention time (min)=5.927, method [7],MS(ESI) 469.1 (M+H); ¹H NMR (300 MHz, DMSO-d₆): δ 8.51 (s, 1H), 8.31 (d,J=8.9 Hz, 1H), 8.20 (d, J=9.8 Hz, 1H), 8.10 (d, J=8.9 Hz, 1H), 7.18 (s,1H), 7.13 (d, J=9.8 Hz, 1H), 5.35 (s, 2H), 3.92 (s, 3H).

1.67. Synthesis ofN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)yl)acetamide

The title compound was prepared from2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetic acid (160mg, 0.588 mmol) and 4-chloro-3(1H-1,2,4-triazol-3-yl)thiophen-2-amine(59 mg, 0.294) mmol) according to protocol A. Retention time(min)=5.046, method [7], MS(ESI) 455.1 (M+H); ¹H NMR (300 MHz, DMSO-d₆):δ 8.62 (s, 1H), 8.30 (d, J=8.9 Hz, 1H), 8.21 (d, J=9.8 Hz, 1H), 8.09 (d,J=8.9 Hz, 1H), 7.20 (s, 1H), 7.13 (d, J=9.8 Hz, 1H), 5.36 (s, 2H).

1.68. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3-fluoroquinolin-8-yl)acetamide

1.68.1 3-Fluoroquinoline

Tert-butylnitrite (4.6 ml, 38.7 mmol) was added dropwise over 15 min toa solution of quinolin-3-amine (4.61 g, 32.0 mmol) andborontrifluoride-etherate (6 ml, 47.3 mmol) in dichlorobenzene (100 ml).The solution was heated to 100° C. After stirring for for 1 h, thesolution was cooled to ambient temperature and the dichlorobenzene wasdecanted leaving 3-fluoroquinoline as a black residue. Method [8]retention time 3.28 min by HPLC (M+ 148).

1.68.2. 3-Fluoro-8-nitroquinoline and 3-fluoro-5-nitroquinoline

A solution of 3:1 concentrated sulfuric acid/concentrated nitric acid(32 ml) was added dropwise to 3-fluoroquinoline (13.04 g, 88.6 mmol) inconcentrated sulfuric acid (100 ml) at 0° C. After stirring for 2 h, thesolution was made alkaline with 10 N aq. NaOH and extracted with diethylether. The combined organic extracts were dried over magnesium sulfate,filtered, and concentrated under reduced pressure to yield3-fluoro-8-nitroquinoline and 3-fluoro-5-nitroquinoline as a yellowsolid, Method [7] retention time 3.50 and 3.92 min by HPLC (M+ 193) and(M+ 193),

1.68.3. 3-Fluoroquinolin-8-amine and 3-fluoroquinolin-5-amine

3-Fluoro-8-nitroquinoline, 3-fluoro-5-nitroquinoline, andtin(II)chloride-dihydrate (68.23 g, 302 mmol) in ethyl acetate (200 ml)was placed into a preheated oil bath at 60° C. After heating for 4 h,the solution was cooled to ambient temperature, diluted with 3 N aq.NaOH, and filtered through a pad of celite. The filtrate was extractedwith ethyl acetate, the combined organic extracts were dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was flash chromatographed with 19:1, 9:1, 17:3, 4:1, 3:1,7:3, and 3:2 hexane:ethyl acetate as the eluant to afford 2.14 g (11%yield over two steps) 3-fluoroquinolin-8-amine and 7.02 g (37% yieldover two steps) of 3-fluoroquinolin-5-amine. Method [6] retention time1.57 and 4.02 min by HPLC (M+ 163) and (M+ 163).

1.68.4. 8-Bromo-3-fluoroquinoline

3-Fluoroquinolin-8-amine (900 mg, 5.55 mmol) was added totert-butylnitrite (1.3 ml, 10.9 mmol) and cupric bromide (1.37 g, 6.13mmol) in acetonitrile (10 ml). The heterogenous mixture was heated to70° C. After stirring for 18 h, the solution was diluted with water andextracted with methylene chloride. The combined organic extracts weredried over magnesium sulfate, filtered, and concentrated. The residuewas purified by flash chromatography (hexane:ethyl acetate) to afford568 mg (45% yield) of 8-bromo-3-fluoroquinoline. Method [7] retentiontime 4.76 min by HPLC (M+ 226 and 228).

1.68.5. 2-(3-fluoroquinolin-8-yl)acetic acid

The title compound was prepared from 8-bromo-3-fluoroquinoline (568 mg,2.51 mmol) and 0.5 M (2-Tert-butoxy-2-oxoethyl)zinc(II) chlorideaccording to Protocol P, accept that the ester was converted to the acidusing NaOH and MeOH in dioxane. Method [7] retention time 2.39 min byHPLC (M+=206).

1.68.6.N-(4-Bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3-fluoroquinolin-8-yl)acetamide

4-Bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (17 mg, 69.4 umol),2-(3-fluoroquinolin-8-yl)acetic acid hydrogen chloride (22 mg, 91.0umol) 2-chloro-2-methylpyridinium iodide (100 mg, 395 umol) andtriethylamine (0.2 ml) in methylene chloride (1 ml) was heated toreflux. After stirring for 1 h, the solution was concentrated and theresidue was purified by HPLC to yieldN-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-y)-2-(3-fluoroquinolin-8-yl)acetamide.Method [7] retention time 5.67 min by HPLC (M+ 432 and 434) and (M+Na454 and 456). ¹H NMR (300 MHz, CDCl₃): δ 12.25 (s, 1H), 8.83 (d, J=3.3Hz, 1H), 7.87 (m, 2H), 7.80 (d, J=6.0 Hz, 1H), 7.73 (s, 1H), 7.66 (t,J=7.8 Hz, 1H), 6.90 (s, 1H), 6.70 (broad s, 2H), 4.56 (s, 2H).

1.69. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3-fluoroquinolin-5-yl)acetamide

The title compound was prepared by converting 3-fluoroquinolin-5-amine(850 mg, 5.24 mmol) into 2-(3-fluoroquinolin-5-yl)acetic acid hydrogenchloride (76 mg, 315 umol) and reaction with4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (34 mg, 139 umol) asoutlined in Example 1.68., above. Method [8] retention time 2.46 min byHPLC (M+ 206). ¹H NMR (300 MHz, CDCl₃): δ 12.35 (s, 1H), 8.89 (d, J=2.7Hz, 1H), 8.26 (d, J=8.7 Hz, 1H), 8.07 (dd, J=9.3 and 2.7 Hz, 1H), 7.83(m, 1H), 7.74 (d, J=6.9 Hz, 1H), 7.59 (s, 1H), 6.93 (s, 1H), 4.33 (s,2H).

1.70. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3-(trifluoromethyl)quinolin-5-yl)acetamide

1.70.1. 3-Iodoquinoline

3-Bromoquinoline (64.00 g, 308 mmol), N,N′-dimethylethylenediamine (13.5ml, 127 mmol), cuprous iodide (12.00 g, 63.0 mmol) and sodium iodide(112 g, 747 mmol) in dioxane (300 ml) was placed into a preheated oilbath at 100° C. After stirring for 18 h, the heterogeneous mixture wasdiluted water and extracted with methylene chloride. The combinedorganic extracts were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was flashchromatographed with methylene chloride as the eluant to afford 68.47 g(87% yield) of 3-iodoquinoline as a yellow solid. Method [8] retentiontime 6.47 min by HPLC (M+=256).

1.70.2. 3-(Trifluoromethyl)quinoline

3-Iodoquinoline (13.65 g, 53.5 mmol), cuprous iodide (21.12, 111 mmol),potassium fluoride (7.11g, 122 mmol), and methyl2-chloro-2,2-difluoroacetate (23 ml, 216 mmol) in dimethylforamide (200ml) was placed into a preheated oil bath at 120° C. After stirring for 6h, the solution was diluted water and extracted with diethyl ether. Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated under reduced pressure. The residue was flashchromatographed with 99:1, 49:1, 24:1, 23:2, 9:1, and 4:1 hexane:ethylacetate as the eluant to afford 3.89 g (37% yield) of3-(trifluoromethyl)quinoline. Method [7] retention time 4.67 min by HPLC(M+ 198).

1.70.3. 8-Bromo-3-(trifluoromethyl)quinoline and5-bromo-3-(trifluoromethyl)quinoline

3-(Trifluoromethyl)quinoline (7.00 g, 35.5 mmol) and N-bromosuccinimide(9.00 g, 50.6 mmol) in concentrated sulfuric acid (50 ml) was heated to50° C. After stirring for 1.5 h, the solution was cooled to ambienttemperature, diluted with saturated aq. sodium sulfite, made alkalinewith 3N aq. sodium hydroxide, and extracted with methylene chloride. Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated under reduced pressure. The residue was flashchromatographed with 99:1, 49:1, 24:1, and 23:2 hexane:ethyl acetate asthe eluant to afford 4.55 g of impure8-bromo-3-(trifluoromethyl)quinoline and 3.89 g (37% yield) of5-bromo-3-(trifluoromethyl)quinoline. Method [8] Retention time 6.75 and7.47 min by HPLC (M+=276 and 278) and (M+=276 and 278).

1.70.4. 2-(3-(Trifluoromethyl)quinolin-5-yl)acetic acid

The title compound was prepared from5-bromo-3-(trifluoromethyl)quinoline (3.59 g, 130.0 mmol) according tothe procedures outlined in Protocol P. Method [7] retention time 2.80min by HPLC (M+=256).

1.70.5.N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3-(trifluoromethyl)quinolin-5-yl)acetamide

The title compound was prepared from4-bromo-3-(4H-1,2,4-triazole-3-yl)thiophen-2-amine (56 mg, 228 umol) and2-(3-trifluoromethylquinolin-5-yl)acetic acid hydrogen chloride (200 mg,784 umol) according to the procedures outlined in Example 1.68.6.,above. Method [7] retention time 5.93 min by HPLC (M+ 482 and 484) and(M+Na 504 and 506). ¹H NMR (300 MHz, CDCl₃): δ 12.45 (s, 1H), 9.23 (s,1H), 8.84 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.03 (m, 1H), 7.85 (d, J=6.9Hz, 1H), 7.74 (s, 1H), 6.95 (s, 1H), 4.38 (s, 2H).

Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3-(trifluoromethyl)quinolin-8-yl)acetamide

1.71.1. 2-(3-Trifluoromethyl)quinolin-8-yl)acetic acid

The title compound was synthesized from2-tert-butoxy-2-oxoethyl)zinc(II) chloride and8-bromo-3-(trifluoromethyl)quinoline (4.55 g) according to protocol P.Method [7] retention time 3.78 min by HPLC (M+ 256).

1.71.2.N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2yl)-2-(3-(trifluoromethyl)quinolin-8-yl)acetamide

The title compound was synthesized from4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (40 mg, 163 umol) and2-(3-fluoroquinolin-8-yl)acetic acid hydrogen chloride (284 mg, 1.11mmol) according to the procedure outlined in Example 1.68, above. Method[7] retention time 7.10 min by HPLC (M+ 482 and 484) and (M+Na 504 and506). ¹H NMR (300 MHz, DMSO-d₆): δ 11.80 (s, 1H), 9.20 (d, J=2.7 Hz,1H), 9.01 (s, 1H), 8.39 (broad s, 1H), 8.25 (d, J=8.1 Hz, 1H), 8.08 (d,J=6.6 Hz, 1H), 7.79 (t, J=7.2 Hz, 1H), 7.21 (s, 1H), 4.38 (s, 2H).

1.72. Synthesis ofN-(4-chloro-3-(3-isopropyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

1.72.1. 5-Chloro-4-hydrazinylthieno[2,3-d]pyrimidine

5-Chloro-4-chlorothieno[2,3-d]pyrimidine (1.38 g, 6.73 mmol) andhydrazine monohydrate (5.0 ml, 103 mmol) in absolute ethanol (20 ml)were heated at 75° C. After stirring for 24 h, the solution wasconcentrated to yield 5-chloro-4-hydrazinylthieno[2,3-d]pyrimidine.Method [6] Retention time 0.35 min by HPLC (M+=201 and 203).

1.72.2.9-Chloro-3-isopropylthieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine

5-Chloro-4-hydrazinylthieno[2,3-d]pyrimidine and1,1,1-triethyoxy-2-methylpropane (10 ml) in ethanol (10 ml) were heatedat 100° C. for 2 h. The solution was concentrated and the residue wasflash chromatographed with 9:1, 4:1, 7:3, and 3:2 hexane:ethyl acetateas the eluant to afford 300 mg (24% yield over 2 steps) of9-chloro-3-isopropylthieno[3,2-d][1,2,4]triazolo[4,3-c]pyrimidine as abrown solid. Method [8] Retention time 4.62 min by HPLC (M+=253 and255).

1.72.3. 4-Chloro-3-(3-isopropyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine

9-chloro-3-isopropylthieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (300mg, 1.19 mmol) and N-methylethane-1,2-diamine (0.50 ml, 5.67 mmol) inmethanol (10 ml) was placed into a preheated oil bath at 60° C. Afterstirring for 15 min, the solution was diluted with saturated ammoniumchloride and extracted with methylene chloride. The combined organicextracts were dried over magnesium sulfate, filtered, and concentratedunder reduced pressure to yield4-chloro-3-(3-isopropyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine. Method[7] Retention time 1.39 min by HPLC (M+=243 and 245).

1.72.4.N-(4-chloro-3-(3-isopropyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

The title compound was prepared from4-chloro-3-(3-isopropyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine (117 mg,482 umol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid(155 mg, 752 umol) using protocol A and was purified by HPLC to yieldN-(4-chloro-3-(3-isopropyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide.Method [7] Retention time 0.35 min by HPLC (M+=431 and 433) and(M+Na=453 and 455). ¹H NMR (300 MHz, DMSO-d₆): δ 12.28 (s, 1H), 8.30 (d,J=5.1 Hz, 1H), 7.76 (d, J=8.7 Hz, 1H), 7.51 (m, 1H), 7.16 (d, J=1.8 Hz,1H), 4.89 (s, 2H) 3.17 (m, 2H), 2.98 (m, 1H), 2.81 (m, 2H), 1.28 (d,J=7.2 Hz, 6H).

1.73. Synthesis ofN-(4-chloro-3-(3-ethyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

1.73.1. 9-Chloro-3-ethylthieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine

5-Chloro-4-hydrazinylthieno[2,3-d]pyrimidine and 1,1,1-triethoxypropane(5 ml) in ethanol (5 ml) was placed into a preheated oil bath at 100° C.for 2 h. The solution was concentrated and the residue was flashchromatographed with 9:1, 4:1, 7:3, and 3:2 hexane:ethyl acetate as theeluant to afford 20 mg of9-chloro-3-ethylthieno[3,2-e][1,2,4]-triazolo[4,3-c]pyrimidine. Method[8] Retention time 6.31 min by HPLC (M+=239 and 241).

1.73.2. 4-Chloro-3-(3-ethyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine

9-Chloro-3-ethylthieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (20 mg,83.8 umol) and N-methylethane-1,2-diamine (0.05 ml, 5.67 umol) inmethanol (2 ml) was placed into a preheated oil bath at 60° C. Afterstirring for 15 min, the solution was diluted with saturated ammoniumchloride and extracted with methylene chloride. The combined organicextracts were dried over magnesium sulfate, filtered, and concentratedunder reduced pressure to afford 18 mg (94% yield) of4-chloro-3-(3-ethyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine as a brownsolid. Method [8] Retention time 2.63 min by HPLC (M+ 229 and 231).

1.73.3.N-(4-chloro-3-(3-ethyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-acetamide

The title compound was prepared from4-chloro-3-(3-ethyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine (18 mg, 78.7umol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (20mg, 97.0 umol) using protocol A. The residue was purified by HPLC toyieldN-(4-chloro-3-(3-ethyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide.Method [8] Retention time 4.47 min by HPLC (M+=417 and 419) and(M+Na=439 and 441). ¹H NMR (300 MHz, CDCl₃): δ 8.39 (dd, J=5.4 and 1.2Hz, 1H), 7.67 (dd, J=8.1 and 1.2 Hz, 1H), 7.49 (dd, J=8.1 and 5.4 Hz,1H), 6.85 (s, 1H), 4.93 (s, 2H), 3.49 (m, 2H), 3.01 (m, 2H), 2.84 (q,J=7.8 Hz, 2H), 1.39 (t, J=7.8 Hz, 3H).

1.74. Synthesis ofN-(4-chloro-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide1.74.1. 9-Chloro-3-methylthieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine

5-Chloro-4-hydrazinylthieno[2,3-d]pyrimidine and 1,1,1-triethoxyethane(10 ml) in ethanol (10 ml) was placed into a preheated oil bath at 100°C. for 2 h. The solution was concentrated and the residue was flashchromatographed with 9:1; 4:1, 7:3, and 3:2 hexane:ethyl acetate as theeluant to afford 92 mg of9-chloro-3-methylthieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidinewhite-pink solid. Method [7] Retention time 3.77 min by HPLC (M+=225 and227).

1.74.2. 4-Chloro-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine

9-Chloro-3-methylthieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (82 mg,365 umol) and N-methylethane-1,2-diamine (0.30 ml, 3.40 mmol) inmethanol (2 ml) was placed into a preheated oil bath at 60° C. Afterstirring for 15 min, the solution was diluted with saturated ammoniumchloride and extracted with methylene chloride. The combined organicextracts were dried over magnesium sulfate, filtered, and concentratedunder reduced pressure to afford 69 mg (88% yield) of4-chloro-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine as a yellowsolid. Method [1] Retention time 0.61 min by HPLC (M+=215 and 217).

1.74.3.N-(4-chloro-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

The title compound was prepared from4-chloro-3-(3-methyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine (69 mg, 321umol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (82mg, 397 umol) using protocol A. The residue was purified by HPLC. Method[8] Retention time 3.40 min by HPLC (M+=403 and 405) and (M+Na=425 and427). ¹H NMR (300 MHz, CDCl₃): δ 8.39 (d, J=5.4 Hz, 1H), 7.67 (d, J=8.4Hz, 1H), 7.49 (dd, J=8.4 and 5.4 Hz, 1H), 6.86 (s, 1H), 5.46 (broad s,2H), 4.95 (s, 2H), 3.49 (m, 2H), 3.01 (m, 2H), 2.50 (s, 3H).

1.75. Synthesis ofN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-acetamide

The title compound was prepared from4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (502 mg, 2.50 mmol)and 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (675 mg,2.49 mmol) using protocol A (626 mg, 55% yield). Method [7] Retentiontime 5.59 min by HPLC (M+=454 and 456) and (M+Na=476 and 478). ¹H NMR(300 MHz, DMSO-d₆): δ 12.23 (s, 1H), 8.38 (broad s, 1H), 8.27 (s, 1H),8.22 (d, J=9.3 Hz, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.70 (d, J=9.3, 1H),7.17 (s, 1H), 6.87 (d, J=9.9 Hz, 1H), 5.31 (s, 2H).

1.76. Synthesis ofN-(4-chloro-3-(1-(3-dimethylamino)propyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

Diisopropyl azodicarboxylate (0.30 ml, 1.52 mmol) was added dropwise toa heterogeneous mixture ofN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide(111 mg, 245 umol), polymer supported triphenylphosphine (500 mg, 1.50mmol) and 3-(dimethylamino)propan-1-ol (300 mg, 2.91 mmol) intetrahydrofuran (5 ml) at 0° C. After stirring for 2 h, theheterogeneous mixture was filtered through a pad of celite andconcentrated under reduced pressure. The residue was purified by HPLC toyieldN-(4-chloro-3-(1-(3-(dimethylamino)propyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide.Method [7] Retention time 4.33 min by HPLC (M+=539 and 541). ¹H NMR (300MHz, DMSO-d₆): δ 12.10 (s, 1H), 8.52 (s, 1H), 8.29 (s, 1H), 8.22 (d,J=9.6 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7, 1H), 7.18 (s,1H), 6.87 (d, J=9.6 Hz, 1H), 5.32 (s, 2H), 4.31 (t, J=6.6 Hz, 2H), 3.09(t, J=6.6 Hz, 2H), 2.75 (s, 6H), 2.17 (m, 2H).

1.77. Synthesis ofN-(4-chloro-3-(1-(2-(dimethylamino)ethyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

The title compound was prepared fromN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl-acetamide(125 mg, 275 umol) and 2-(dimethylamino)ethanol (311 mg, 3.49 mmol)using the procedures described in Example 1.76 except that the reactionwas run at 60° C. (rather than 0° C.). The residue was purified by HPLCto yieldN-(4-chloro-3-(1-(2-(dimethylamino)ethyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide.Method [7] Retention time 4.40 min by HPLC (M+=525 and 527) and(M+Na=547 and 549). ¹H NMR (300 MHz, DMSO-d₆): δ 8.41 (s, 1H), 8.28 (s,1H), 8.22 (d, J=9.3 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7,1H), 7.16 (s, 1H), 6.87 (d, J=9.3 Hz, 1H), 5.32 (s, 2H), 4.28 (t, J=6.0Hz, 2H), 2.64 (t, J=6.0 Hz, 2H), 2.15 (s, 6H).

1.78. Synthesis ofN-(4-chloro-3-(1-(3-(4-methylpiperazin-1-yl)propyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

The title compound was prepared fromN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide(108 mg, 248 umol) and 3-(4-methylpiperazin-1-yl)propan-1-ol (350 mg,2.21 mmol) using the procedures described in Example 1.76. HPLCpurification gaveN-(4-chloro-3-(1-(3-(4-methylpiperazin-1-yl)propyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide.Method [7] retention time 4.27 min by HPLC (M+=594 and 596). ¹H NMR (300MHz, DMSO-d₆): δ 12.13 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 8.22 (d,J=9.9 Hz, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.17 (s,1H), 6.87 (d, J=9.3 Hz, 1H), 5.32 (s, 2H), 4.25 (t, J=6.6 Hz, 2H), 2.95(broad m, 10H), 2.73 (s, 3H), 1.97 (m, 2H).

1.79. Synthesis ofN-(4-chloro-3-(1-(3-morpholinopropyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

The title compound was prepared fromN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide(110 mg, 242 umol) and 3-morpholinopropan-1-ol (350 mg, 2.41 mmol) usingthe procedure described in Example 1.76. HPLC purification gaveN-(4-chloro-3-(1-(3-morpholinopropyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide.Method [7] Retention time 4.58 min by HPLC (M+=581 and 583) and(M+Na=603 and 605). ¹H NMR (300 MHz, DMSO-d₆): δ 12.10 (s, 1H), 8.47 (s,1H), 8.26 (s, 1H), 8.20 (d, J=9.3 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.70(d, J=9.3 Hz, 1H), 7.16 (s, 1H), 6.86 (d, J=9.3 Hz, 1H), 5.30 (s, 2H),4.30 (t, J=7.2 Hz, 2H), 3.20 (broad m, 10H), 1.20 (m, 2H).

1.80 Synthesis ofN-(4-chloro-3-(1-(3-(pyrrolidin-1-yl)propyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)-acetamide

The title compound was prepared fromN-(4-chloro-3(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide(110 mg, 242 umol) and 3-(pyrrolidin-1-yl)propan-1-ol (325 mg, 2.52mmol) using the procedures described in Example 1.76. HPLC purificationgaveN-(4-chloro-3-(1-(3-(pyrrolidin-1-yl)propyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide.Method [7] Retention time 4.65 min by HPLC (M+=565 and 567). ¹H NMR (300MHz, DMSO-d₆): δ 12.10 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.21 (d,J=9.3 Hz, 1H), 7.91 (d, J=9.3 Hz, 1H), 7.70 (d, J=9.3 Hz, 1H), 7.17 (s,1H), 6.86 (d, J=9.3 Hz, 1H), 5.31 (s, 2H), 4.31 (t, J=6.6 Hz, 2H), 3.20(broad m, 6H), 2.18 (m, 2H), 1.99 (m, 2H), 1.83 (m, 2H).

1.81. Synthesis of2-(6-bromo-2-oxoquinolin-1(2H)-yl)-N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)acetamide

1.81.1. 2-(6-Bromo-2-oxoquinolin-1(2H)-yl)acetic acid

6-Bromoquinolin-2(1H)-one (5.03 g, 22.5 mmol) was subjected to protocolK with ethyl bromoacetate instead of methyl bromoacetate to afford 6.96g, (100% yield) of ethyl 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetate as awhite solid. Method [7] Retention time 4.79 min by HPLC (M+=310 and 312)and (M+Na=332 and 334). The acetate (318 mg, 1.03 mmol) was subjected tothe protocol in Example 1.53.4 to afford 228 mg (83% yield) of2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetic acid as a white solid. Method[8] Retention time 4.79 min by HPLC (M+=282 and 282) and (M+Na=304 and306).

1.81.2.2-(6-Bromo-2-oxoquinolin-1(2H)-yl)-N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)acetamide

The title compound was prepared from4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (55 mg, 224 umol) and2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetic acid (85 mg, 301 umol)according to protocol A. HPLC purification gave2-(6-bromo-2-oxoquinolin-1(2H)-yl)-N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)acetamide.Method [7] retention time 5.41 min by HPLC (M+=508, 510, and 512). ¹HNMR (300 MHz, CDCl₃): δ 7.80 (m, 2H), 7.70 (s, 1H), 7.63 (dd, J=9.0 and2.4 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H), 6.94 (m, 2H), 5.31 (s, 2H).

1.82. Synthesis of2-(6-bromo-2-oxoquinolin-1(2H)-yl)-N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)acetamide

The title compound was prepared from4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (115 mg, 573 umol)and 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetic acid (135 mg, 479 umol)according to protocol A. HPLC purification gave2-(6-bromo-2-oxoquinolin-1(2H)-yl)-N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)acetamide.Method [7] Retention time 5.30 min by HPLC (M+=464, 466, and 468) arethe major peak intensities. ¹H NMR (300 MHz, CDCl₃): δ 7.80 (m, 2H),7.70 (s, 1H), 7.64 (dd, J=9.0 and 2.4 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H),6.94 (d, J=9.3 Hz, 1H), 6.82 (s, 1H), 5.30 (s, 2H).

Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetamide

1.83.1. Ethyl 2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetate

Ethyl 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetate (2.37 g, 7.64 mmol)cuprous cyanide (8.87 g, 99.0 mmol), andtetrakis(triphenylphosphine)palladium(0) (3.50 g, 3.03 mmol) indimethylforamide (100 ml) was placed into a preheated oil bath at 140°C. After stirring for 24 h, the solution was diluted with water andextracted with ethyl acetate. The combined organic extracts were driedover magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was flash chromatographed with 9:1, 4:1, 7:3, and3:2 methylene chloride:ethyl acetate as the eluant to afford 0.74 g (38%yield) of ethyl 2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetate. Method [7]retention time 2.87 min by HPLC (M+ 257).

1.83.2. 2-(6-Cyano-2-oxoquinolin-1(2H)-yl)acetic acid

Ethyl 2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetate was subjected to theprotocol in Example 1.53.4 to afford 550 mg (83% yield) of2-(6-cyano-2-oxoquinolin-1(21H)-yl)acetic acid as a yellow solid. Method[7] retention time 2.44 min by HPLC (M+ 229).

1.83.3.N-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetamide

The title compound was prepared from4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (253 mg, 1.03 mmol)and 2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetic acid (325 mg, 1.42 mmol0according to protocol A. HPLC purification gaveN-(4-bromo-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetamide.Method [7] Retention time 4.00 min by HPLC (M+=455 and 457). ¹H NMR (300MHz, DMSO-d₆): δ 8.42 (broad s, 1H), 8.37 (s, 1H), 8.13 (d, J=9.9 Hz,1H), 7.98 (d, J=9.0 Hz, 1H), 7.70 (d, J=9.9 Hz, 1H), 7.27 (s, 1H), 6.87(d, J=9.3 Hz, 1H), 5.30 (s, 2H).

1.84. Synthesis ofN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetamide

The title compound was prepared from4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (215 mg, 1.07 mmol)and 2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetic acid (325 mg, 1.42 mmol)using protocol A. HPLC purification gaveN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetamide.Method [7] Retention time 3.83 min by HPLC (M+=411 and 413). ¹H NMR (300MHz, DMSO-d₆): δ 8.37 (s, 2H), 8.13 (d J=9.9 Hz, 1H), 7.98 (d, J=8.7 Hz,1H), 7.70 (d, J=9.3 Hz, 1H), 7.17 (s, 1H), 6.86 (d, J=9.9 Hz, 1H), 5.31(s, 2H).

1.85. Synthesis ofN-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-isoquinolin-4-yl)acetamide

To a solution of 4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (50mg, 0.2 mmol) and 2-(isoquinolin-4-yl)acetic acid (56 mg, 0.3 mmol) inmethylene chloride (2 mL) were added Hunig's base (i.e.,N,N-diisopropylethylamine) (71 uL, 0.4 mmol) and HBTU (133 mg, 0.35mmol). The heterogeneous reaction mixture was homogenous after 3 h. Thereaction was quenched with saturated aqueous ammonium chloride and theaqueous was extracted with methylene chloride. The organic phase waswashed with brine and dried over sodium sulfate. The resulting solutionwas concentrated to provide a pale red solid, which was purified bycolumn chromatography using 3.5% MeOH/CH₂Cl₂. LCMS: retention time 1.955min using analytical method [7] with an M+Na of 414.0 19.0 mg (15%yield): white solid. ¹H-NMR (300 MHz, CDCl₃): δ 9.34 (s, 1H), 8.66 (s,1H), 8.07 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.75 (m, 1H), 7.65(m, 2H), 6.88 (d, J=0.5 Hz, 1H), 4.30 (s, 2H). ¹³C-NMR (75 MHz, CDCl₃):δ 168.3, 153.2, 144.8, 142.8, 135.0, 131.5, 128.7, 128.4, 127.8, 123.5,122.9, 116,2, 104,7, 38.7.

1.86. Synthesis ofN-(3-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3,3-difluoro-2-oxoindolin-1-yl)acetamide

1.86.1. 3,3-Difluoroindolin-2-one

A 100 mL reaction flask was charged with indoline-2,3-dione (0.88 g, 6.0mmol). DCM (40 mL) was added, followed by DAST (2.4 g, 15.0 mmol). Thereaction was stirred for 16 h before being quenched by the addition of 2mL MeOH. The organic reaction mixture was rinsed with water and theorganic layer was dried over sodium sulfate. The solution wasconcentrated under reduced pressure to give 3,3-difluoroindolin-2-one(1.0 g, 98%). LC-MS of this crude showed the desired m/z of 170.0 at amethod [1] retention time of 1.673 min in.

1.86.2. tert-Butyl 2-(3,3-difluoro-2-oxoindolin-1-yl)acetate

The title compound was prepared from 3,3-difluoroindolin-2-one usingprotocol K except using tert-butyl 2-bromoacetate to give crudetert-butyl 2-(3,3-difluoro-2-oxoindolin-1yl)acetate as a yellow oil.LCMS method [1] showed an M+Na peak of 306.1 with a retention time of2.502 min.

1.86.3. 2-(3,3-Difluoro-2-oxoindolin-1-yl)acetic acid

A 30 mL reaction vial was charged with tert-butyl2-(3,3-difluoro-2-oxoindolin-1-yl)acetate (275 mg, 1 mmol) as a yellowoil. DCM (3 mL) was added, followed by an equal volume of formic acid.The reaction was stirred for 16 h. The reaction mixture was concentratedunder reduced pressure to give 2-(3,3-difluoro-2-oxoindolin-1-yl)aceticacid as a yellow solid. The desired M+H (228) was observed in the LCMSusing the method [1] with a retention time of 1.652 min.

1.86.4.N-(4-Bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3,3-difluoro-2-oxoindolin-1-yl)acetamide

The title compound was prepared from2-(3,3-difluoro-2-oxoindolin-1-yl)acetic acid (50 mg, 0.22 mmol),4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (45 mg, 0.18 mmol)using protocol A. HPLC purification gaveN-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(3,3-difluoro-2-oxoindolin-1-yl)acetamide(12 mg) as a white solid (m/z 454.0, retention of 5.696 min in [7]).¹H-NMR (300 MHz, CDCl₃): δ 13.1 (s, 1H), 7.82 (s, 1H), 7.70 (dd, J=7.5,1.5 Hz, 1H), 7.50 (td, J=7.9, 1.2 Hz, 1H), 6.99 (s, 1H), 6.92 (d, J=7.9Hz, 1H), 4.71 (s, 2H).

1.87. Synthesis ofN-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(7-(trifluoromethyl)quinolin-5-yl)acetamideandN-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(5-(trifluoromethyl)quinolin-7-yl)acetamide

1.87.1. 7-Bromo-5-(trifluoromethyl)quinoline and5-bromo-7-(trifluoromethyl)quinoline

3-bromo-5-(trifluoromethyl)aniline (11.7 g, 48.5 mmol) was taken up inglycerol (7.2 mL) and conc. H₂SO₄ (13 mL). Nitrobenzene (5.0 mL) andFeSO₄.7H₂O (800 mg, 2.88 mmol) were added, and the mixture was slowlywarmed to 130° C. for 4 h. Isolation led to a 3:2 mixture ofregioisomers, which was used without further purification in thesubsequent reaction. HPLC method [4], retention time 2.53 and 2.59 min;MS(ESI) 278.0 (MH+, ⁸¹Br).

1.87.2. tert-Butyl 2-(5-(trifluoromethyl)quinolin-7-yl)acetate andtert-butyl 2-(7-(trifluoromethyl)quinolin-5-yl)acetate

The title compounds were prepared from7-bromo-5-(trifluoromethyl)quinoline and5-bromo-7-(trifluoromethyl)quinoline (550 mg, 2.0 mmol) using protocolP. Flash chromatography (10-30% EtOAc/hexanes elution) afforded theproduct as a brown oil (400 mg, 64%). HPLC method [7], retention time5.61 and 5.74 min; MS(ESI) 312.0 (MH+).

1.87.3. 2-(5-(Trifluoromethyl)quinolin-7-yl)acetic acid and2-(7-(trifluoromethyl)quinolin-5-yl)acetic acid

A mixture of tert-butyl 2-(5-(trifluoromethyl)quinolin-7-yl)acetate andtert-butyl 2-(7-trifluoromethyl)quinolin-5-yl)acetate (400 mg, 1.3 mmol)was dissolved in glacial AcOH (8 mL) and 6N HCl (8 mL). The mixture washeated to 70° C. for 1 h, then 80° C. for an additional hr. The reactionmixture was concentrated in vacuo to afford the crude title compounds,which were used without further purification. HPLC method [4], retentiontime 1.29 min; MS(ESI) 256.0 (MH+).

1.87.4.N-(4-Bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(7-(trifluoromethyl)quinolin-5-yl0acetamideandN-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(5-(trifluoromethyl)quinolin-7-yl)acetamide

2-(5-trifluoromethyl)quinolin-7-yl)acetic acid and the mixture of2-(7-(trifluoromethyl)quinolin-5-yl)acetic acid (28.3 mg, 0.11 mmol) and4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (23 mg, 0.094 mmol)were treated according to protocol A. The crude product mixture waspurified by HPLC to affordN-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(5-trifluoromethyl)quinolin-7-yl)acetamideandN-(4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(7-trifluoromethyl)quinolin-5-yl)acetamide.LCMS method [13], retention time (min) 10.100 and 10.386. MS(ESI) 482.0(MH+, ⁷⁹Br); ¹H NMR (300 MHz, CD₃OD): δ 9.01 (dd, J=4.3, 1.6 Hz, 1H),8.62 (d, J=8.4 Hz, 1H), 8.41 (s, 1H), 7.98 (s, 1H), 7.70 (dd, J=8.7, 4.3Hz, 1H), 4.50 (s, 2H).

1.88 Synthesis of N-(4-bromo-3-(4H,1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-(trifluoromethyl)quinolin-7-yl)acetamide

1.88.1. tert-Butyl 2-(2-(trifluoromethyl)quinolin-7-yl)acetate

The title compound was prepared from7-bromo-2-(trifluoromethyl)quinoline (Keller, H. and Schlosser, M.Tetrahedron 1996, 52: 4637-4644) (45 mg, 0.163 mmol) using protocol Pand was purified by flash chromatography (10-30% EtOAc/hexanes elution)to afforded a brown oil. HPLC method [5], retention time 1.875 min;MS(ESI) 312.0 (MH+).

1.88.2. 2-(2-(Trifluoromethyl)quinolin-7-yl)acetic acid

tert-Butyl 2-(2-(trifluoromethyl)quinolin-7-yl)acetate was dissolved inglacial AcOH (0.8 mL) and 6 N HCl (0.8 mL) and heated to 80° C. for 2hr. The reaction mixture was concentrated in vacuo to afford the crudeproduct, which was used without further purification. HPLC method [4],retention time=1.874 min; MS(ESI) 256.1 (MH+).

1.88.3.N-(4-Bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-(trifluoromethyl)quinolin-7-yl)acetamide

The title compound was synthesized via protocol B from2-(2-(trifluoromethyl)quinolin-7-yl)acetic acid and4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine, using HOAt instead ofHOBt. HPLC purification afforded the product as a white solid. HPLCmethod [7], retention time 8.68 min; MS(ESI) 484.2 (MH+, ⁸¹Br); ¹H NMR(300 MHz, CD₃OD): δ 8.76 (d, J=9.5 Hz, 1H), 8.25 (d, J=9.0 Hz, 1H), 7.96(dd, J=8.7, 7.3 Hz, 1H), 7.92-7.81 (m, 1H), 7.11-6.97 (m, 1H), 4.45 (s,2H).

1.89. Synthesis ofN-(4-cyano-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

1.89.1. Thieno[3,2-e][1,2,4]-triazolo[1,5-c]pyrimidine-9-carbonitrile

9-Bromothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (1.16 g, 4.55 mmol)was dissolved in DMF (23 mL), and copper(I) cyanide (817 mg, 9.1 mmol)was added. This mixture was heated to 150° C. for 23 h, whereupon thereaction mixture was concentrated under reduced pressure, and theresidue purified by flash chromatography. LCMS method [4], retentiontime=0.890 min; MS(ESI) 202.0 (MH+); ¹H NMR (300 MHz, CDCl₃): δ 9.36 (s,1H), 8.57 (s, 1H), 8.32 (s, 1H.

1.89.2. 5-Amino-4-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile

Thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-9-carbonitrile (251 mg,1.25 mmol) was dissolved in MeOH (6.2 mL), andN¹-methylethane-1,2-diamine (0.22 mL, 2.5 mmol) was added. This washeated to 60° C. for 20 min, then immediately cooled in an ice bath.Saturated NH₄Cl (30 mL) was added, then the aqueous mixture wasextracted with 10% iPrOH/CHCl₃ (3×). The organic layers were combined,dried (MgSO₄), filtered and concentrated under reduced pressure to givethe title compound as a single peak on LC/MS: method [4], retentiontime=0.658 min; MS(ESI) 192.0 (MH+).

1.89.3.N-(4-Cyano-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

The title compound was synthesized according to protocol A from5-amino-4-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (69 mg, 0.364mmol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acidhydrochloride (89 mg, 0.367 mmol). HPLC purification afforded desiredproduct as a white solid. LCMS method [11], retention time=6.22 min;MS(ESI) 380.1 (MH+); ¹H NMR (300 MHz, CD₃OD): δ 8.52 (s, 1H), 8.28 (d,J=5.2 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.4,5.3 Hz, 1H), 5.01 (s, 2H), 3.37 (t, J=7.6 Hz, 2H), 2.99 (t, J=7.6 Hz,2H).

1.90. Synthesis ofN-(4-cyano-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

N-(4-cyano-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide(180 mg, 0.475 mmol) was dissolved in MeOH/CH₂Cl₂ (1:1, 4 mL total),TMSCHN₂ (Aldrich, 2.0 M in diethyl ether, 8 mL, 16 mmol) was added atrt. This was stirred for 4 h, whereupon the reaction mixture wasconcentrated under reduced pressure. The crude residue was purified byHPLC to give a white solid as a trifluoroacetic acid salt: method [11],retention time=7.56 min; MS(ESI) 394.2 (MH+); ¹H NMR (300 MHz, CD₃OD):8.41 (s, 1H), 8.25 (d, J=5.0 Hz, 1H), 7.87 (s, 1H), 7.72 (d, J=8.7 Hz,1H), 7.52-7.42 (m, 1H), 4.98 (s, 2H), 3.97 (s, 3H), 3.40-3.20 (m, 2H),2.96 (t, J=8.3 Hz, 2H).

1.91. Synthesis ofN-(4-chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

1.91.1. 4-Chloro-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine

This compound was made via a sequence analogous to the synthesis of4-bromo-3-(4H-1,2,4-triazolo-3-yl)thiophen-2-amine: method [11],retention time=3.73 min; MS(ESI) 201.0 (MH+, ³⁵Cl); ¹H NMR (300 MHz,DMSO-d₆): δ 13.68 (br s, 1H), 8.35 (br s, 1H), 7.14 (br s, 2H), 6.48 (s,1H).

1.91.2.N-(4-Chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

The titled compound was synthesized from4-chloro-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine and2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid via protocolA. LCMS method [4], retention time=1.035; MS(ESI) 389.1 (MH+, ³⁵Cl).

1.91.3.N-(4-Chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

The titled compound was synthesized fromN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamideand TMSCHN₂. HPLC purification afforded a white solid. LCMS method [11],retention time=7.322 min; MS(ESI) 403.2 (MH+, ³⁵Cl); ¹H NMR (300 MHz,CD₃OD): δ 8.43 (s, 1H), 8.29 (d, J=5.3 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H),7.59 (t, J=7.1 Hz, 1H), 6.94 (s, 1H), 4.98 (s, 2H), 3.98 (s, 3H), 3.36(t, J=7.5 Hz, 2H), 2.97 (dd, J=8.2 6.3 Hz, 2H).

1.92. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinolin-8-l)acetamide

To a mixture of 2-(quinolin-8-yl)acetic acid (35.6 mg, 0.19 mmol) and4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (27.6 mg, 0.11 mmol)in methylene chloride (1.0 mL) and triethylamine (0.1 mL) was added2-chloro-1-methylpyridinium iodide (46.5 mg, 0.18 mmol) at rt. Afterstirring for 15 min, the reaction mixture was concentrated under reducedpressure. Purification by flash chromatography (silica, 40:60 ethylacetate/hexane) gaveN-(5-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(quinolin-8-l)acetamide(12 mgs, 26%). The desired product was submitted to prep HPLC forfurther purification. Retention time (min)=3.486, method [7], MS(ESI)415.9 (M+H). ¹H NMR (CDCl₃): δ 12.42 (s, 1H), 9.09 (d, J=1.7 Hz, 1H),8.40 (d, J=8.5 Hz, 1H) 7.96 (d, J=8.6 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H),7.73 (s, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.58 (d,J=4.5 Hz, 1H), 6.86 (s, 1H), 4.62 (s, 2H).

1.93. Synthesis of2-(benzo[d]thiazol-7-yl)-N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophene-2-yl)acetamide

The title compound was prepared from 2-(benzo[d]thiazol-7-yl)acetic acid(25.5 mg, 0.13 mmol) and4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (22.3 mg, 0.093 mmol)according to protocol A. The crude product was purified by prep HPLC.LCMS Retention time (min)=4.075, method [7], MS(ESI) 421.9 (M+H). ¹H NMR(CDCl₃): δ 12.39 (s, 1H), 9.02 (s, 1H), 8.22 (d, J=6.6 Hz, 1H),7.65-7.61 (m, 1H), 7.54 (s, 1H), 7.55-7.49 (m, 1H), 6.90 (s, 1H), 4.19(s, 2H).

1.94. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7-fluoroquinolin-5-yl)acetamide1.94.1. N-(3-Bromo-5-fluorophenyl)acetamide

To a mixture of tris(dibenzylideneacetone)dipalladium (0.20 g, 0.22mmol), 9,9-dimethyl-4,5-bis(diphenylphosphine)xanthene (0.13, 0.22 mmol)and cesium carbonate (5.0 g, 15.41 mmol) under N₂ gas was addedacetamide (0.90, 14.73 mmol), 1,3-dibromo-5-fluorobenzene (2.8 g, 10.83mmol) and dioxane (22 mL). The reaction mixture was heated at 80° C.overnight and concentrated under reduced pressure. Purification by flashchromatography (silica, 50:50 ethyl acetate/hexane) gaveN-(3-bromo-5-fluorophenyl)acetamide (3.51 g, quantitative). Retentiontime (min)=1.945, method [4], MS(ESI) 232.0 (M+H).

1.94.2. 3-Bromo-5-fluoroaniline hydrochloride

To a solution of N-(3-bromo-5-fluorophenyl)acetamide (3.5 g, 15.13mmole) in absolute ethanol (40 mL) was added HCl (50 mL of a 11% aqueoussolution). The reaction mixture was stirred while refluxing in an oilbath set at 110° C. overnight. Conc hydrochloric acid (5 mL) was addedand stirred for an additional 5 h prior to concentrating under reducepressure. The resulting 3-bromo-5-fluoroaniline hydrochloride (2.9 g,85% yield) was used in the next reaction without further purification.Retention time (min)=2.077, method [4], MS(ESI) 192.0 (M+H).

1.94.3. 5-Bromo-7-fluoroquinoline and 7-bromo-5-fluoroquinoline

To 3-bromo-5-fluoroaniline hydrochloride (2.9 g, 12.89 mmol) was addedglycerol (1.9 mL, 25.99 mmol), nitrobenzene (2.3 mL), sulfuric acid (3.5mL) and iron (II) sulfate heptahydrate (0.23 g, 0.82 mmol). The reactionmixture was placed in an oil bath set at 80° C. and stirred overnightfollowed by basification with 12N NaOH and extraction withdichloromethane. The organic phase was collected dried (sodium sulfate),filtered and concentrated under reduced pressure. Purification by flashchromatography (silica, 50:50 ethyl acetate/hexane) gave5-bromo-7-fluoroquinoline and 7-bromo-5-fluoroquinoline (1.03 g, 30%)Retention time (min)=1.877 and 1.967, method [4], MS(ESI) 227.9 (M+H).

1.94.4. tert-Butyl 2-(7-fluoroquinolin-5-yl)acetate and tert-Butyl2-(5-fluoroquinolin-7-yl)acetate

The title compounds were prepared from 5-bromo-7-fluoroquinoline and7-bromo-5-fluoroquinoline (1.0 g, 4.356 mmol) using protocol P.Purification by flash chromatography (silica, 30:70 ethylacetate/hexane) gave a mixture of tert-butyl2-(7-fluoroquinolin-5-yl)acetate and tert-butyl2-(5-fluoroquinolin-7-yl)acetate (0.500 g, 42%) Retention time(min)=1.559 and 1.725, method [4], MS(ESI) 262.1 (M+H).

1.94.5. 2-(7-Fluoroquinolin-5-yl)acetic acid

To a solution of tert-butyl 2-(7-fluoroquinolin-5-yl)acetate andtert-butyl 2-(5-fluoroquinolin-7-yl)acetate (0.50 g, 1.91 mmol) inacetic acid (5 mL) was added 4M hydrochloric acid in 1,4-dioxane (10mL). The reaction mixture was heated in an oil bath set at 60° C. undercondenser with N₂ (g) inlet overnight. The mixture was concentratedunder reduced pressure and purified by flash chromatography (silica,60:40 ethyl acetate/hexane following by 20:80 methanol/dichloromethane).Further purification and separation by prep HPLC yielded the singleregio-isomer 2-(7-fluoroquinolin-5-yl)acetic acid (0.025 g, 6%).Retention time (min)=0.337, method [4], MS(ESI) 206.1 (M+H).

1.94.6.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7-fluoroquinolin-5-yl)acetamide

The title compound was prepared from 2-(7-fluoroquinolin-5-yl)aceticacid (0.025 g, 0.122 mmol) and4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl-amine (0.20 g, 0.083mmol) according to protocol A. The desired product was submitted to prepHPLC for further purification. Retention time (min)=2.33, method [7],MS(ESI) 434.0 (M+H). ¹H NMR (300 MHz, CDCl₃): δ 11.79 (s, 1H), 8.94 (d,J=4.0 Hz, 1H), 8.54 (d, J=8.1 Hz, 1H) 8.38 (s, 1H broad), 7.80 (d,J=10.1 Hz, 1H), 7.70 (d, J=10.1 Hz, 1H), 7.59-7.55 (m 1H), 7.22 (s, 1H),4.47 (s, 2H).

1.95. Synthesis ofN-(4-cyano-3-(1H-1,2,3-triazol-1-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

1.95.1. 5-Nitro-4-(1H-1,2,3-triazol-1-yl)thiophene-3-carbonitrile and5-nitro-4-(2H-1,2,3-triazol-2-yl)thiophene-3-carbonitrile

A mixture of 4-bromo-5-nitrothiophene-3-carbonitrile (0.53 g, 2.26mmol), 1H-1,2,3-triazole (20 μL, 0.35 mmol) and sodium bicarbonate(0.050 g, 0.60 mmol) in DMF (0.6 mL) were stirred in an oil bath set at110° C. under condenser with N₂ (g) inlet for 2 h. The reaction mixturewas quenched with H₂O and extracted with ethyl acetate. The organicphase was collected, dried (sodium sulfate), filtered and concentratedunder reduced pressure. Purification by flash chromatography (silica,30:70 ethyl acetate/hexane) gave the regio-isomer of each nitrointermediate (0.138 g and 0.116 g, 67% of 1:1 mixture). Retention time(min)=1.260 and 1.692, method [4], MS(ESI) 222.0 (M+H).

1.95.2. 5-Amino-4-(1H-1,2,3-triazol-1-yl)thiophene-3-carbonitrile

5-amino-4-(1H-1,2,3-triazol-1-yl)thiophene-3-carbonitrile was preparedfrom 5-nitro-4-(1H-1,2,3-triazol-1-yl)thiophene-3-carbonitrile (0.12 g,0.52 mmol) according to protocol P. Retention time (min)=2.114, method[4], MS(ESI) 192.0 (M+H).

1.95.3.N-(4-Cyano-3-(1H-1,2,3-triazol-1-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.072 g, 0.27mmol) and 5-amino-4-(1H-1,2,3-triazol-1-yl)thiophene-3-carbonitrile(0.025 g, 0.13 mmol) according to protocol A. The crude product waspurified by prep HPLC. LCMS retention time (min)=5.505, method [7],MS(ESI) 445.1 (M+H). ¹H NMR (300 MHz, CDCl₃): δ 11.17 (s, 1H), 8.41 (s,1H), 7.91-7.87 (m, 3H), 7.79 (d, J=9.0 Hz, 1H), 7.67 (s, 1H), 7.48 (d,J=9.0 Hz, 1H), 5.26 (s, 2H).

1.96. Synthesis ofN-(4-cyano-3-(2H-1,2,3-triazol-2-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

1.96.1. 5-Amino-4-(2H-1,2,3-triazol-2-yl)thiophene-3-carbonitrile

5-amino-4-(2H-1,2,3-triazol-2-yl)thiophene-3-carbonitrile was preparedfrom 5-nitro-4-(2H-1,2,3-triazol-2-yl)thiophene-3-carbonitrile (0.11 g,0.62 mmole) according to protocol P. Retention time (min)=1.304, method[4], MS(ESI) 192.1 (M+H).

1.96.2.N-(4-Cyano-3-(2H-1,2,3-triazol-2-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

N-(4-cyano-3-(2H-1,2,3-triazol-2-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamidewas prepared from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)aceticacid (0.15 g, 0.56 mmol) and5-amino-4-(2H-1,2,3-triazol-2-yl)thiophene-3-carbonitrile (0.070 g, 0.37mmol) according to protocol A. The crude product was purified by prepHPLC. Retention time (min)=6.5, method [7], MS(ESI) 467.1 (M+Na). ¹H NMR(300 MHz, CDCl₃): δ 11.50 (s, 1H), 7.93-7.85 (m, 4H), 7.83 (s, 1H), 7.64(s, 1H), 7.60 (d, J=8.5 Hz, 1H), 6.95 (d, J=9.7 Hz, 1H), 5.29 (s, 2H).

1.97. Synthesis ofN-(4-bromo-3-(2H-1,2,3-triazol-2-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

1.97.1. 2-(4-Bromo-2-nitrothiophen-3-yl)-2H-1,2,3-triazole

A mixture of 3,4-dibromo-2-nitrothiophene (1.5 g, 5.23 mmol),1H-1,2,3-triazole (0.30 mL, 5.18 mmol) and potassium bicarbonate (0.54g, 5.36 mmol) in DMF (13 mL) were stirred in an oil bath set at 110° C.under condenser with N₂ (g) inlet for 1 h. The reaction mixture wasquenched with H₂O and extracted with ethyl acetate. The organic phasewas collected, dried (sodium sulfate), filtered and concentrated underreduced pressure. Purification by flash chromatography (silica, 30:70ethyl acetate/hexane) gave the regio-isomer nitro intermediate ofinterest (0.518 g, 36%). Retention time (min)=1.950, method [4], MS(ESI)276.9 (M+H).

1.97.2. 4-Bromo-3-(2H-1,2,3-triazol-2-yl)thiophene-2-amine

A mixture of 2-(4-bromo-2-nitrothiophene-3-yl)-2H-1,2,3-triazole (0.59g, 2.15 mmol), iron powder (0.75 g, 13.38 mmol), glacial acetic acid(8.4 mL) and H₂O (1.2 mL) was heated in an oil bath set at 70° C. undercondenser with N₂ (g) inlet for 1 h. Purification by flashchromatography (silica, 40:60 ethyl acetate/hexane) gave4-bromo-3-(2H-1,2,3-triazol-2-yl)thiophene-2-amine (0.35 g, 66%).Retention time (min)=1.540, method [4], MS(ESI) 246.9 (M+H).

1.97.3.N-(4-Bromo-3-(2H-1,2,3-triazol-2-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.31 g, 1.14mmol) and 4-bromo-3-(2H)-1,2,3-triazol-2-yl)thiophene-2-amine (0.35 g,1.42 mmol) according to protocol A. The desired product was submitted toprep HPLC for further purification. Retention time (min)=6.9, method[7], MS(ESI) 498.0 (M+H). ¹H NMR (CDCl₃): δ 10.56 (s, 1H), 7.90-7.89 (m,2H), 7.86 (s, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.66 (d, J=8.9 Hz, 1H), 6.97(s, 1H), 6.92 (d, J=8.9 Hz, 2H), 5.16 (s, 2H).

1.98. Synthesis ofN-(4-chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetamide

1.98.1.N-(4-Chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetic acid (0.13 g, 0.62 mmol) and4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (0.22 g, 1.12 mmol)according to protocol A and purified by prep HPLC. Retention time(min)=1.010, method [4], MS(ESI) 389.0 (M+H).

1.98.2.N-(4-Chloro-3-(1-methyl-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetamide

To a solution ofN-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetamide(0.047, 0.12 mmol) in DMF (0.4 mL) was added potassium carbonate (0.041g, 0.30 mmol) and iodomethane (17 uL, 0.27 mmol). After 2 h the reactionmixture was partitioned between H₂O and ethyl acetate. The organic phasewas collected, dried (sodium sulfate), filtered and concentrated underreduced pressure. The desired product was submitted to prep HPLC forfurther purification. Retention time (min)=4.407, method [8], MS(ESI)403.1 (M+H). ¹H NMR (CDCl₃): δ 12.40 (s, 1H), 8.32 (d, J=5.1 Hz, 1H),8.07 (s, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.41 (d, J=5.1 Hz, 1H), 7.39 (d,J=5.1 Hz, 1H), 6.81 (s, 1H), 4.89 (s, 2H), 4.02 (s, 3H), 3.47-3.42 (m,2H), 3.03-2.98 (m, 2H).

Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(8-fluoroisoquinolin-5-yl)acetamide

1.99.1. 5-Bromo-8-nitroisoquinoline

KNO₃ (5.1 g, 50 mmol) was suspended in sulfuric acid (40 mL) and chilledto 0° C. 5-bromoisoquinoline (4 g, 19.2 mmol) was added slowly over thecourse of 20 minutes. The yellow, heterogeneous solution was brought topH 8 by slow addition of ammonium hydroxide. Yellow solid was filteredoff and recrystallized from methanol to give 7.5 g of5-bromo-8-nitroisoquinoline. LCMS showed an m/z of 253.0/255.0 with aretention time of 1.797 min, method [1].

1.99.2. 5-Bromoisoquinolin-8-amine

A 3-neck flask was charged with 5-bromo-8nitroisoquinoline (4 g, 15.8mmol) and dissolved in MeOH (50 mL). A condenser was affixed and themixture was heated to 100° C. Aqueous (20 mL) solution of ammoniumchloride (4.12 g, 79 mmol) was added slowly, followed by iron powder (3g, 53.7 mmol). The heterogeneous mixture was stirred at 100° C. for 3 h.LCMS confirmed complete reduction to the amine. The mixture was filteredand the solution was concentrated under reduced pressure to give a brownsolid as crude product (2.4 g, 68%). LCMS showed an m/z of 225.0/223.0with a retention time of 0.767 min, method [1].

1.99.3. 5-Bromo-8-fluoroisoquinoline

To a solution of 8-amino-5-bromoisoquinoline in 48% HBF4 (30 mL) at 0°C. was slowly added an aqueous (10 mL) solution of NaNO₂ (172 mg, 2.5mmol). The reaction mixture was stirred at 0° C. for 1 h and was thenconcentrated under reduced pressure to give a dark residue. The darkresidue was heated to 150° C. for 16 h. The resulting dark oil wascooled to 23° C. quenched with ammonium hydroxide and extracted withDCM. The organic solution was concentrated and the resulting dark solidwas recrystallized from EtOAc/Hexanes. The desired product (100 mg) wasin the mother liquor while the by-product was filtered away as a solid.LCMS showed an m/z of 228.0/226.0 with a retention time of 1.318 min,method [1].

1.99.4. 2-(8-Fluoroisoquinolin-5-yl)acetic acid

A 30 mL reaction vial was flame dried and charged with isopropylamine(0.67 mL, 4.8 mmol) in toluene (3 mL). The solution was chilled to 0° C.before a 1.5 M solution of nBuLi (4.8 mmol, 3.2 mL) was added. Pd₂(dba)₃catalyst (184 mg, 0.2 mmol) was added, followed by ligand2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (160 mg, 0.4mmol), and t-butylacetate (464 mg, 4 mmol). After 15 min, a toluene (3mL) solution of 5-bromo-8-fluoroisoquinoline (200 mg, 0.9 mmol) wasadded. The reaction was stirred for 16 h while warming to 23° C. Thecrude mixture was purified by column chromatography (3% MeOH/DCM) togive tert-butyl 2-(8-fluoroisoquinolin-5-yl)acetate (140 mg). LCMSshowed an m/z of 262.1 with a retention time of 1.469 min, method [1].

To a solution of the above ester (200 mg) in DCM (2 mL) was added formicacid (3 mL). The reaction was scaled with a Teflon cap and heater to 50°C. for 16 h. The solvent was removed and the crude product was usedwithout further purification. LCMS showed an m/z of 206.1 with aretention time of 0.437 min, method [1].

1.99.5.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(8-fluoroisoquinolin-5-yl)acetamide

The title compound was prepared from 2-(8-fluoroisoquinolin-5-yl)aceticacid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine usingprotocol B. Retention time (min)=1.987, method [7], MS(ESI) 432.0 (M+H);¹H NMR (300 MHz, CD₃OD): δ 9.74 (s, 1H), 8.66 (d, J=6.6 Hz, 1H), 8.30(d, J=6.1 Hz, 1H), 8.20 (b s, 1H), 8.1 (dd, J=8.24, 5.5 Hz, 1H), 7.67(dd, J=9.9, 7.7 Hz, 1H), 7.1 (s, 1H), 4.46 (s, 2H).

Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetamide

1.100.1 (E)-Ethyl 3-(2-amino-5-(trifluoromethoxy)phenyl)acrylate

To a mixture of 2-bromo-4-(trifluoromethoxy)aniline (1.00 mmol),triethylamine (1.5 mmol) and P(p-tol)₃ (0.40 mmol) in DMF (0.5 M) in aglass pressure tube under nitrogen gas were added ethyl acrylate (1.0mmol) and palladium acetate (0.20 mmol). The tube was sealed and heatedto 120° C. for 18 h. The resulting solution was concentrated undervacuum and purified by column chromatography. Retention time(min)=2.467, method [1], MS(ESI) 276.1 (M+H).

1.100.2. 6-(Trifluoromethoxy)quinolin-2(1H)-one

To a stirring mixture of (E)-ethyl3-(2-amino-5-trifluoromethoxy)phenyl)acrylate (2.2 mmol) in 4N HCl indioxane (25 mL) was added concentrated HCl (2 mL). The resulting mixturewas warmed to 100° C. overnight. The reaction mixture was cooled to rtand then slowly quenched with a cold saturated NaHCO₃ solution untilpH>7. The product was extracted with EtOAc and used without furtherpurification. Retention time (min)=1.804, method [1], MS(ESI) 230.1(M+H).

1.100.3. Methyl 2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetate

Methyl 2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetate wasprepared from 6-(trifluoromethoxy)quinolin-2(1H)-one according toProtocol K. Retention time (min)=2.083, method [1], MS(ESI) 302.1 (M+H).

1.100.4. 2-(2-Oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid

To a stirring solution of methyl2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetate (1.2 mmol) inTHF/water (2:1) was added LiOH. H₂O (8.1 mmol). The resulting mixturewas stirred overnight. The crude product mixture was slowly acidifiedwith 1N HCl solution and then extracted with EtOAc. The organic phasewas separated, dried (MgSO₄), filtered and concentrated under vacuum togive 2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid.Retention time (min)=1.783, method MS(ESI) 288.1 (M+H).

1.100.5.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-oxo-6-trifluoromethoxy)quinolin-1(2H)-yl)acetic acid (40 mg, 0.14mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (28 mg, 0.11mmol) according to protocol A. Retention time (min)=6.06 method [7],MS(ESI) 514.0 (M+H); ¹H NMR (300 MHz, CD₃Cl): δ 7.85 (d, J=9.35Hz, 1H),7.73 (s, 1H), 7.50 (s, 1H), 7.44-7.41 (m, 1H), 7.35-7.33 (m, 1H), 6.97(d, J=9.9 Hz, 1H), 6.95 (s, 1H), 5.31 (s, 2H).

1.101. Synthesis ofN-(5-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetamide

1.101.1. 8-Chlorothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine

To a stirring mixture of thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine(123 mg, 0.7 mmol) in HOAc (1 mL) was added NCS (200 mg, 1.5 mmol),Pd(OAc)₂ (48 mg, 0.21 mmol). The reaction mixture was stirred at 120° C.overnight. The reaction was neutralized with a saturated NaHCO₃ solutionand extracted with DCM. This product was purified via an isco column togive 8-chlorothieno[3,2-c][1,2,4]triazolo[4,3-c]pyrimidine as the majorproduct. Retention time (min)=1.663, method [1], MS(ESI) 211.0 (M+H).

1.101.2. 5-Chloro-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine

To a stirring mixture of8-chlorothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (60 mg, 0.285mmol) in MeOH (10 mL) was added N-methylethyl 1,2-diamine (106 mg, 1.4mmol). The resulting mixture was warmed to 60° C. for 1 hr. The reactionmixture was cooled to rt and then diluted with DCM. This mixture wasthen washed several times with a saturated NH₄Cl solution. The organiclayer was dried over MgSO₄, filtered, and concentrated under reducedpressure to give 5-chloro-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine.This amine was taken directly to the next coupling reaction withoutfurther purification. Retention time (min)=1.227, method [1], MS(ESI)201.1 (M+H).

1.101.3.N-(chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

The title compound was synthesized from2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid and5-chloro-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine according to protocolA. Retention time (min)=6.178, method [7], MS(ESI) 454.1 (M+H).); ¹H NMR(300 MHz, CDCl₃): δ 11.93 (b s, 1H), 8.0 (s, 1H), 7.92-7.86 (m, 2H),7.84-7.81 (m, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.17 (s, 1H), 6.97 (d, J=9.34Hz, 1H), 5.30 (s, 2H).

1.102. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-5-(trifluoromethoxy)quinolin-1(2H)-yl)acetamide

1.102.1. (E)-Ethyl 3-(2-amino-6-(trifluoromethyl)phenyl)acrylate

The aryl halide (2.1 mmol) and P(PPh)₃ (0.82 mmol) were dissolved intriethylamine (3.15 mmol) in a glass pressure tube and nitrogen gas wasbubbled through the solution via a gas dispersion tube for 10 minutes.Ethyl acrylate (2.3 mmol) and palladium acetate (0.41 mmol) were addedto the reaction mixture and the tube was sealed and placed into an oilbath pre-heated to 120° C. for 18 h. The resulting solution wasconcentrated under vacuum and purified via an isco column. Retentiontime (min)=2.416, method [1], MS(ESI) 260.1 (M+H).

1.102.2. 5-(trifluoromethyl)quinolin-2(1H)-one

To a stirring mixture of (E)-ethyl3-(2-amino-6-(trifluoromethyl)phenyl)acrylate in 4N HCl in dioxane (25mL) was added concentrated HCl (2 mL). The resulting mixture was warmedto 100° C. overnight. The reaction mixture was cooled to rt and thenslowly quenched with a cold saturated NaHCO₃ solution until pH>7. Anormal aqueous extraction with EtOAc was followed. The crude mixture wastaken directly to the next reaction without further purification.Retention time (min)=1.892, method [1], MS(ESI) 214.0 (M+H).

1.102.3. Methyl 2-(2-oxo-5-(trifluoromethyl)quinolin-1(2H)-yl)acetate

Methyl 2-(2-oxo-5-(trifluoromethyl)quinolin-1(2H)-yl)acetate wasprepared from 5-(trifluoromethoxy)quinolin-2(1H)-one (T. Sakamoto, Y.Kondo, H. Yamanka, Chem. Phar. Bull., 33, 1985, 4764) according toprotocol K. Retention time (min)=2.02, method [1], MS(ESI) 286.1 (M+H).To a stirring solution of the acetate (0.33 mmol) in THF/water (10:1)was added LiOH.H₂O (2.33 mmol). The resulting mixture was stirredovernight. The crude product mixture was slowly acidified with 1N HClsolution and then extracted with EtOAc. The organic phase was separated,dried (MgSO₄), filtered, and concentrated under vacuum to give2-(2-oxo-5-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid. Retentiontime (min)=1.710, method [1], MS(ESI) 272.1 (M+H).

1.102.4.N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-5-(trifluoromethoxy)quinolin-1(2H)-yl)acetamide

The title compound was synthesized from2-(2-oxo-5-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid and4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocolA. Retention time (min)=5.810, method [7], MS(ESI) 498.0 (M+H). ¹H NMR(300 MHz, CD₃Cl): δ 8.30-8.23 (m, 1H), 7.67 (s, 1H), 7.65-7.262 (m, 1H),7.63 (s, 1H), 7.57-7.53 (m, 1H), 7.05 (d, J=9.9 Hz, 1H), 6.95 (s, 1H),5.37 (s, 2H).

1.103. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

1.103.12-(2-Oxo-6-(trifluoromethyl)-3,4-dihydroquinolin-1-(2H)-yl)acetic acid

To a stirring mixture of2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid in Pd/C wasadded MeOH. The reaction mixture was placed under an atmosphere ofhydrogen (balloon) for several hours. The product mixture was filteredthrough a plug of celite. The plug was washed several times with EtOAc.The mixture was concentrated under reduced pressure and the crude aminewas taken directly to the next reaction without further purification.Retention time (min)=1.841, method [1], MS(ESI) 274.1 (M+H).

1.103.2.N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

The title compound was synthesize from2-(2-oxo-6-(trifluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)acetic acidand 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according toprotocol A. Retention time (min)=6.373, method [7], MS(ESI) 500.0 (M+H);¹H NMR (300 MHz, CD₃Cl): δ 7.90 (s, 1H), 7.50 (s, 1H), 7.49 (d, J=6.6Hz, 1H), 7.03 (3, J=9.34, 1H), 6.90 (s, 1H), 4.92 (s, 2H), 3.20-3.14 (m,2H), 2.93-2.90 (m, 2H).

1.104. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-ethynyl-2-oxoquinolin-1(2H)-yl)acetamide

1.104.1. Methyl2-(2-oxo-6-((trimethylsilyl)ethynyl)quinolin-1(2H)-yl)acetate

Methyl 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetate (0.67 mmol), CuI (0.67mmol) and PdCl₂(PPh₃)₂ (0.40 mmol) were dissolved in triethylamine (3mL) in a glass pressure tube and nitrogen gas was bubbled through thesolution via a gas dispersion tube for 5 minutes. Ethynyltrimethylsilane(3.5 mmol) was added to the reaction mixture and the tube was sealed andplaced into an oil bath pre-heated to 80° C. for 8 h. The resultingsolution was concentrated under vacuum and purified via an isco column.Retention time (min)=2.759, method [1], MS(ESI) 314.1 (M+H).

1.104.2. 2-(6-Ethynyl-2-oxoquinolin-1(2H)-yl)acetic acid

Methyl 2-(2-oxo-6-((trimethylsilyl)ethynyl)quinolin-1(2H)-yl)acetate(0.128 mmol) was subjected to the protocol in Example 1.53.4, exceptwith LiOH.H₂O instead of NaOH. Retention time (min)=1.435, method [1],MS(ESI) 228.1 (M+H).

1.104.3.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-96-ethynyl-2-oxoquinolin-1(2H)-yl)acetamide

The title compound was synthesized from2-(6-ethyl-2-oxoquinolin-1(2H)-yl)acetic acid and and4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocolA. Retention time (min)=6.563, method [7], MS(ESI) 454.0 (M+H); ¹H NMR(300 MHz, DMSO-d₆): δ 8.51 (s, 1H), 8.07 (d, J=9.35 Hz, 1H), 8.01-7.97(m, 1H), 7.68-7.63 (m, 1H), 7.50 (d, J=8.80 Hz, 1H), 7.30 (s, 1H), 6.80(d, J=9.9 Hz, 1H), 5.27 (s, 2H), 4.23 (s, 1H).

1.105. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-methylimidazo[2,1-b]thiazol-3-yl)acetamide

The title compound was synthesized from2-(6-methylimidazo[2,1-b]thiazol-3-yl)acetic acid and4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocolA. Retention time (min)=8.520, method [6], MS(ESI) 423.0 (M+H); ¹H NMR(300 MHz, CD₃Cl): δ 8.12 (s, 1H), 7.35 (s, 1H), 7.22 (s, 1H), 7.0 (s,1H), 4.15 (s, 2H), 2.50 (s, 3H).

1.106. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(imidazo[1,2-a]pyridin-5-yl)acetamide

1.106.1 tert-Butyl 2-(imidazo[1,2-a]pyridin-5-yl)acetate

The title compound was prepared from 5-bromoimidazo[1,2-a]pyridine (1.0g) according to protocol P. The crude product mixture was purified vianormal phase chromatography to give tert-butyl2-(imidazo[1,2-a]pyridin-5-yl)acetate. Method [1], MS(ESI) 233.1 [M+H],Retention time=0.951 min.

1.106.2. 2-(Imidazo[1,2-a]pyridin-5-yl)acetic acid

To a stirring mixture of tert-butyl2-(imidazo[1,2-a]pyridin-5-yl)acetate (200 mg) in HOAc (5 mL) was added6N HCl (5 mL). The reaction mixture was warmed to 80° C. for 2 h. Thecrude product mixture was concentrated under reduced pressure anddirectly taken to the next reaction without further purification. Method[1], MS(ESI) 177.1 [M+H], Retention time=0.303 min.

1.106.3.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(imidazo[1,2-a]pyridin-5-yl)acetamide

N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(imidazo[1,2-a]pyridin-5-yl)acetamidewas synthesized from 2-(imidazo[1,2-a]pyridin-5-yl)acetic acid and4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocolA. Retention time (min)=7.958, method [6], MS(ESI) 403.0 (M+H); ¹H NMR(300 MHz, CD₃OD): δ 8.46 (b s, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.12 (d,J=2.2 Hz, 1H), 8.08-7.96 (m, 2H), 7.58 (d, J=7.2 Hz, 1H), 7.16 (s, 1H),4.64 (s, 2H).

1.107. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7-fluoro-2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

1.107.1. 2-Bromo-5-fluoro-4-(trifluoromethyl)aniline

To a stirring mixture of 3-fluoro-4-(trifluoromethyl)aniline (1.5 g) inDCM (12 mL) at room temperature was added dropwise a solution of NBS(1.5 g) in DCM (24 mL) over 15 min. The reaction mixture was stirred atrt for 1.5 h. The product mixture was concentrated under reducedpressure to one half of its original volume. The white solid wasfiltered off and the crude product mixture was further purified viacolumn chromatography. Retention time (min)=2.490, method [1], MS(ESI)257.9 (M+H).

1.107.2. (E)-Ethyl3-(2-amino-4-fluoro-5-(trifluoromethyl)phenyl)acrylate

2-Bromo-5-fluoro-4-(trifluoromethyl)aniline (0.97 mmol) and P(o-tol)₃(0.40 mmol) were dissolved in triethylamine (2.0 mL) in a glass pressuretube and nitrogen gas was bubbled through the solution via a gasdispersion tube for 10 minutes. Ethyl acrylate (1.0 mmol) and palladiumacetate (0.20 mmol) were added to the reaction mixture and the tube wassealed and placed into an oil bath pre-heated to 85° C. for 18 h. Theresulting solution was concentrated under vacuum and purified via anisco column. Retention time (min)=2.504, method [1], MS(ESI) 278.0 (M+).

1.107.3. 7-Fluoro-6-(trifluoromethyl)quinolin-2(1H)-one

To a stirring mixture of (E)-ethyl3-(2-amino-4-fluoro-5-(trifluoromethyl)phenyl)acrylate in 4N HCl indioxane (10 mL) was added concentrated HCl (2 mL). The resulting mixturewas warmed to 100° C. overnight. The reaction mixture was cooled to rtand then slowly quenched with a cold saturated NaHCO₃ solution untilpH>7. A normal aqueous extraction with EtOAc was followed. The crudemixture was taken directly to the next reaction without furtherpurification. Retention time (min)=1.887, method [1], MS(ESI) 232.0(M+H).

1.107.4. Methyl2-(7-fluoro-2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetate

The title compound was prepared from7-fluoro-6-(trifluoromethyl)quinolin-2(1H)-one (T. Sakamoto, Y. Kondo,H. Yamanaka, Chem. Phar. Bull., 33, 1985, 4764) according to protocol K.Retention time (min)=2.224, method [1], MS(ESI) 304.0 (M+H).

1.107.5. 2-(7-Fluoro-2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)aceticacid

To a stirring solution of methyl methyl2-(7-fluoro-2-oxo-6-(trifluoromethyl)-quinolin-1(2H)-yl)acetate (0.59mmol) in THF/water (5:1) was added LiOH.H₂ (3.0 mmol). The resultingmixture was stirred overnight. The crude product mixture was slowlyacidified with 1N HCl solution and then extracted with EtOAc. Theorganic phase was separated, dried (MgSO₄), filtered, and concentratedunder vacuum to give2-(7-fluoro-2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid.Retention time (min)=1.90, method [1], MS(ESI) 290.1 (M+H).

1.107.6(N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7-fluoro-2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(7-fluoro-2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamidewas synthesized from2-(7-fluoro-2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid and4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocolA. Retention time (min)=6.276, method [7], MS(ESI) 516.0 (M+H); ¹H NMR(300 MHz, DMSO-d₆): δ 8.54 (b s, 1H), 8.37 (d, J=8.24 Hz, 1H), 8.20 (d,J=9.34 Hz, 1H), 7.89 (d, J=13.72 Hz, 1H), 7.31 (s, 1H), 6.81 (d, J=9.34Hz, 1H), 5.28 (s, 2H).

1.108. Synthesis ofN-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroisoquinolin-5-yl)acetamide

1.108.1 5-Bromo-6-fluoroisoquinoline

To a stirring mixture of 6-fluoroisoquinoline in H₂SO₄ (5 mL) at 0° C.was added solid NBS (1.5 EQ) slowly over 5 min. The reaction mixture wasreacted at 0° C. for 1 h. To this reaction mixture was added NBS (0.5EQ). The cold bath was then removed. The reaction mixture was reacteduntil all the starting material was consumed. To this reaction mixturewas neutralized with a cold solution of NaOH (5N) until the pH of thismixture >10. The white solid was filtered off and dissolved in DCM andwashed with a solution of NaOH (1N). The organic layer was dried overMgSO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified via a column to give 5-bromo-6-fluoroisoquinoline.Retention time (min)=2.810, method [3], MS(ESI) 226.0 (M+H).

1.108.2. tert-Butyl 2-(6-fluoroisoquinolin-5-yl)acetate

The title compound was prepared from 5-bromo-6-fluoroisoquinoline (290mg) using protocol P. The crude product was purified via normal phasechromatography to give tert-butyl 2-(6-fluoroisoquinolin-5-yl)acetate.Method [1], MS(ESI) 262.1 [M+], Retention time=1.503 min.

1.108.3 2-(6-Fluoroisoquinolin-5-yl)acetic acid

To a stirring mixture tert-butyl 2-(6-fluoroisoquinolin-5-yl)acetate(150 mg) in HOAc (5 mL) was added 6N HCl (5 mL). The reaction mixturewas warmed to 100° C. for 3 h. The crude product mixture wasconcentrated under reduced pressure and directly taken to the nextreaction without further purification. Method [1], MS(ESI) 206.1 [M+H],Retention time=0.313 min.

1.108.4.N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroisoquinolin-5-yl)acetamide

N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(6-fluoroisoquinolin-5-yl)acetamidewas prepared from 2-(6-fluoroisoquinolin-5-yl)acetic acid and4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocolA. Retention time (min)=1.901, method [7], MS(ESI) 432.0 (M+H); ¹H NMR(300 MHz, DMSO-d₆) 11.96 (b s, 1H), 9.58 (s, 1H), 8.64 (d, J=6.05 Hz,1H), 8.46-8.41 (m, 1H), 8.24 (d, J=6.05 Hz, 1H), 7.84 (t, J=9.34 Hz,1H), 7.27 (s, 1H), 4.46 (s, 2H).

EXAMPLE 2 Thiophene Thiazole Analogs 2.1. Synthesis of2-(Isoquinolin-5-yl)-N-(2-(4-methylthiazol-2-yl)thiophen-3-yl)acetamide(42)

2.1.1. 4-Methyl-2-(3-nitrothiophen-2-yl)thiazole

4-Methyl-2-(3-nitrothiophen-2-yl)thiazole was prepared from2-chloro-3-nitrothiophene (219 mg, 1.34 mmol) and4-methyl-2-(tributylstannyl)thiazole (520 mg, 1.34 mmol) according toprotocol E. Retention time (min)=2.462, method [1], MS(ESI) 227.0 (M+H).

2.1.2. 2-(4-Methylthiazol-2-yl)thiophen-3-amine

2-(4-Methylthiazol-2-yl)thiophen-3-amine was prepared from4-methyl-2-(3-nitrothiophen-2-yl)thiazole (69 mg, 0.305 mmol) accordingto protocol F. Retention time (min)=1.828, method [1], MS(ESI) 197.0(M+H).

2.1.3.2-(Isoquinolin-5-yl)-N-(2-(4-methylthiazol-2-yl)thiophen-3-yl)acetamide

2-(Isoquinolin-5-yl)-N-(2-(4-methylthiazol-2-yl)thiophen-3-yl)acetamidewas prepared from 2-(isoquinolin-5-y)acetic acid (63 mg, 0.341 mmol) and2-(4-methylthiazol-2-yl)thiophen-3-amine (67 mg, 0.341 mmol) accordingto protocol A. Retention time (min)=3.130, method [7], MS(ESI) 366.0(M+H); ¹H NMR (300 MHz, CDCl₃): δ 11.55 (s, 1H), 9.64 (s, 1H), 8.60 (d,J=6.8 Hz, 1H), 8.39 (d, J=6.6 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.05-8.08(m, 2H), 7.88-7.91 (m, 1H), 7.24 (d, J=5.5 Hz, 1H), 6.74 (s, 1H), 4.31(s, 2H), 2.45 (s, 3H).

2.2. Synthesis of2-(isoquinolin-5-yl)-N-(2-thiazol-4-yl)thiophen-3-yl)acetamide (43)

2.2.1. 4-(3-Nitrothiophen-2-yl)thiazole

4-(3-Nitrothiophen-2-yl)thiazole was prepared from4-(tributylstannyl)thiazole (0.51 g, 1.31 mmol) and2-chloro-3-nitrothiophene (0.21 g, 1.31 mmol) according to protocol E.Retention time (min)=2.012, method [1], MS(ESI) 212.9 (M+H).

2.2.2. 2-(Thiazol-4-yl)thiophen-3-amine

2-(Thiazol-4-yl)thiophen-3-amine was prepared from4-(3-nitrothiophen-2-yl)thiazole (151 mg, 0.828 mmol)) according to F.Retention time (min)=0.544, method [1], MS(ESI) 183.0 (M+H).

2.2.3. 2-(Isoquinolin-5-yl)-N-(2-(thiazol-4-yl)thiophen-3-yl)acetamide

2-(Isoquinolin-5-yl)-N-(2-(thiazol-4-yl)thiophen-3-yl)acetamide wasprepared from 2-(isoquinolin-5-yl)acetic acid (120 mg, 0.641 mmol) and2-(thiazol-4-yl)thiophen-3-amine (117 mg, 0.641 mmol) according toprotocol A. Retention time (min)=2.147, method [7], MS(ESI) 352.0 (M+H);¹H NMR (300 MHz, CDCl₃): δ 10.99 (s, 1H), 9.63 (s, 1H), 8.59 (d, J=5.9Hz, 1H), 8.43 (d, J=1.6 Hz, 1H), 8.23-8.42 (m, 2H), 8.04-8.08 (m, 2H),7.90 (dd, J=8.1, 7.2 Hz, 1H), 7.18-7.23 (m, 2H), 4.31 (s, 2H).

2.3. Synthesis of2-(2-Oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)-N-(2-(thiazol-4-yl)thiophen-3-yl)acetamide(44)

2.3.1. Methyl 2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetate

The title compound was prepared from3,4-dihydro-1,6-naphthyridin-2(1H)-one (0.84 g, 5.67 mmol) usingprotocol K to give methyl2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetate. Retention time(min)=0.341, method [1], MS(ESI) 221.0 (M+H).

2.3.2. 2-(2-Oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetic acid

Aqueous 1N HCl (2 mL) was added to a solution of methyl2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetate (1.24 g, 5.67mmol) in acetic acid (5 mL) and the resulting mixture was heated to 60°C. for 4 h. The solution was concentrated under vacuum to give2-(2-Oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetic acid. Retentiontime (min)=0.275, method [1], MS(ESI) 207.0 (M+H).

2.3.3.2-(2-Oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)-N-(2-(thiazol-4-yl)thiophen-3-yl)acetamide

The title compound was prepared from2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetic acid (65 mg, 0.32mmol) and 2-(thiazol-4-yl)thiophen-3-amine (57 mg, 0.32 mmol) accordingto protocol A. Retention time (min)=1.471, method [7], MS(ESI) 371.1(M+H); ¹H NMR (300 MHz, CDCl₃): δ 11.48 (s, 1H), 8.87 (d, J=1.8 Hz, 1H),8.48-8.76 (m, 1H), 7.99 (d, J=5.4 Hz, 1H), 7.37 (d, J=1.8 Hz, 1H),7.27-2.28 (m, 2H), 7.23 (d, J=5.4 Hz, 1H), 4.91 (s, 2H), 3.20-3.25 (m,2H), 2.96-3.01 (m, 2H).

2.4. Synthesis of2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)-N-(2-(thiazol-4-yl)thiophen-3-yl)acetamide(45)

The title compound was prepared from2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (88 mg, 0.43 mmol) and2-(thiazol-4-yl)thiophen-3-amine (70 mg, 0.43 mmol) according toprotocol A. Retention time (min)=5.703, method [7], MS(ESI) 370.0 (M+H);¹H NMR (300 MHz, CDCl₃): δ 11.2 (s, 1H), 8.49 9d, J=2.7 Hz, 1H), 8.13(d, J=5.4 Hz, 1H), 7.19-7.25 (m, 4H), 7.02-7.08 (m, 2H), 4.81 (s, 2H),3.05-3.09 (m, 2H), 3.2.85-2.89 (m, 2H).

2.5. Synthesis of2-(isoquinolin-5-yl)-N-(2-(2-methoxythiazol-4-yl)thiophen-3-yl)acetamide(46)

2.5.1. 2-Methoxy-4-(3-nitrothiophen-2-yl)thiazole

2-Methoxy-4-(3-nitrothiophen-2-yl)thiazole was prepared from2-methoxy-4-(tributylstannyl)thiazole (1.0 g, 2.47 mmol) and2-chloro-3-nitrothiophene (0.404 g, 2.47 mmol) according to protocol E.Retention time (min)=2.516, method [1], MS(ESI) 242.9 (M+H).

2.5.2. 2-(2-Methoxythiazol-4-yl)thiophen-3-amine

2-(2-Methoxythiazol-4-yl)thiophen-3-amine was prepared from2-methoxy-4-(3-nitrothiophen-2-yl)thiazole (209 mg, 0.862 mmol)according to protocol F. Retention time (min)=1.17, method [1], MS(ESI)213.0 (M+H).

2.5.3.2-(Isoquinolin-5-yl)-N-(2-(2-methoxythiazol-4-yl)thiophen-3-yl)acetamide

The title compound was prepared from 2-(isoquinolin-5-yl)acetic acid (72mg, 0.36 mmol) and 2-(2-methoxythiazol-4-yl)thiophen-3-amine (78 mg,0.36 mmol) according to protocol A. Retention time (min)=3.237, method[7], MS(ESI) 382.0 (M+H); ¹H NMR (300 MHz, CDCl₃): δ 10.99 (s, 1H), 9.69(s, 1H), 8.60 (d, J=6.5 Hz, 1H), 8.39 (d, J=6.5 Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 8.06 (d, J=7.3 Hz, 1H), 7.96 (d, J=5.5 Hz, 1H), 7.89 (dd,J=8.4, 7.3, 1H), 7.15 (d, J=5.5, 1H), 6.70 (s, 1H), 4.26 (s, 2H), 4.17(s, 3H).

2.6. Synthesis ofN-(2-(2-chlorothiazol-4-yl)thiophen-3-yl)-2-(isoquinolin-5-yl)acetamide(47)

2.6.1. 2-Chloro-4-(3-nitrothiophen-2-yl)thiazole

A solution of 2-methoxy-4-(3-nitrothiophen-2-yl)thiazole (403 mg, 1.66mmol) in POCl₃ (2 mL) was heated at 60° C. for 1 h to 100° C. for afurther 2 h. The resulting solution was cooled to room temperature anddiluted with cold H₂O then saturated aqueous sodium bicarbonate. Themixture was extracted with methylene chloride and the combined organicphases were dried (Na₂SO₄), filtered and concentrated under vacuum togive 2-chloro-4-(3-nitrothiophen-2-yl)thiazole. Retention time(min)=2.550, method [1], MS(ESI) 246.9 (M+H).

2.6.2. 2-(2-Chlorothiazol-4-yl)thiophen-3-amine

2-(2-Chlorothiazol-4-yl)thiophen-3-amine was prepared from2-chloro-4-(3-nitrothiophen-2-yl)thiazole (307 mg, 1.24 mmol) accordingto protocol F. Retention time (min)=1.579, method [1], MS(ESI) 216.9(M+H),

2.6.3.N-(2-(2-chlorothiazol-4-yl)thiophen-3-yl)-2-(isoquinolin-5-yl)acetamide

The title compound was prepared from 2-(isoquinolin-5-yl)acetic acid(218 mg, 1.11 mmol) and 2-(2-chlorothiazol-4-yl)thiophen-3-amine (241mg, 1.11 mmol) according to protocol A. Retention time (min)=3.049,method [7], MS(ESI) 385.89 (M+H); ¹H NMR (300 MHz, CD₃OD): δ 9.54 (s,1H), 8.56 (d, J=6.4 Hz, 1H), 8.39 (d, J=6.4 Hz, 1H), 8.31 (d, J=8.1 Hz,1H), 8.16 (d, J=6.8 Hz, 1H), 7.94 (dd, J=8.1, 7.2 Hz, 1H), 7.73 (d,J=5.5 Hz, 1H), 7.45 (s, 1H), 7.37 (d, J=5.5 Hz, 1H), 4.39 (s, 2H).

2.7. Synthesis of2-(Isoquinolin-5-yl)-N-(2-(thiazol-2-yl)thiophen-3-yl)acetamide (48)

2.7.1. 2-(Thiazol-2-yl)thiophen-3-amine

2-(3-Nitrothiophen-2-yl)thiazole was synthesized from2-chloro-3-nitrothiophene according to protocol E except that2-(tributylstannyl)thiazole was used. Method [1], MS(ESI) 212.9 [M+H],Retention time=2.163 min. 2-(Thiazol-2-yl)thiophen-3-amine wassynthesized from 2-(3-nitrothiophen-2-yl)thiazole according to protocolF. Method [1], MS(ESI) 183 [M−H], Retention time=1.718 min.

2.7.2. 2-(Isoquinolin-5-yl)-N-(2-(thiazol-2-yl)thiophen-3-yl)acetamide

The title compound was prepared from 2-(thiazol-2-yl)thiophen-3-amineand 2-(isoquinolin-5-yl)acetic acid according to protocol A. PreparativeHPLC gave2-(isoquinolin-5-yl)-N-(2-(thiazol-2-yl)thiophen-3-yl)acetamide. Method[7], MS(ESI) 352.1 [M+H], Retention time=2.59 min; ¹H-NMR (300 MHz,CDCl₃): δ 11.32 (s, 1H), 8.26 (d, J=8.2 Hz, 1H), 8.10-8.09 (m, 1H), 8.07(s, 1H), 7.94 (t, J=7.7 hz, 1H), 7.35 (d, J=3.3 Hz, 1H), 7.31-7.24 (m,4H), 7.10 (d, J=3.3 Hz, 1H), 4.33 (s, 2H).

2.8. Synthesis of2-(isoquinolin-5-yl)-N-(2-(5-methylthiazol-2-yl)thiophen-3-yl)acetamide(49)

2.8.1. 2-(5-Methylthiazol-2-yl)thiophen-3-amine

This amine was prepared from 2-chloro-3-nitrothiophene using protocols Eand F. Method [1], MS(ESI) 227.0 [M+H], Retention time=2.538 min.

2.8.2.2-(Isoquinolin-5-yl)-N-(2-(5-methylthiazol-2-yl)thiophen-3-yl)acetamide

The title compound was prepared from 2-(isoquinolin-5-yl)acetic acid and2-(5-methylthiazol-2-yl)thiophen-3-amine using Protocol A. Method [7],MS(ESI) 366.0 [M+H], Retention time=3.157 min; ¹H-NMR (300 MHz, CDCl₃):δ 11.24 (s, 1H), 9.67 (s, 1H), 8.57 (d, J=6.6 Hz, 1H), 8.30 (d, J=6.6Hz, 1H), 8.26 (d, J=8.24 Hz, 1H), 8.08-8.04 (m, 2H), 7.96-7.91 (m, 1H),7.20 (d, J=5.5 Hz, 1H), 6.97 (d, J=1.1 Hz, 1H), 4.31 (s, 2H), 2.43 (d,J=1.1 Hz, 3H).

2.9. Synthesis of2-(4-(3-(piperidin-1-yl)propoxy)phenyl)-N-(2-(thiazol-4-yl)thiophen-3-yl)acetamide(50)

2.9.1. 2-(Thiazol-4-yl)thiophen-3-amine

This amine was prepared from 2-chloro-3-nitrothiophene using Protocols Eand F except that 4-(tributylstannyl)thiazole was used. Method [1],MS(ESI) 183.0 [M+H], Retention time=0.518 min.

2.9.2.2-(4-(3-(Piperidin-1-yl)propoxy)phenyl)-N-(2-(thiazol-4-yl)thiophen-3-yl)acetamide

The title compound was prepared from 2-(thiazol-4-yl)thiophen-3-amineand 2-(4-(3-(piperidin-1-yl)propoxy)phenyl)acetic acid using protocol X.Method [7], MS(ESI) 442.1 [M+H], Retention time=3.586 min; ¹H-NMR (300MHz, CDCl₃): δ 10.8 (s, 1H), 8.54-8.53 (m, 1H), 8.13-8.11 (m, 1H),7.33-7.30 (m, 2H), 7.25-7.17 (m, 2H), 6.90 (d, J=8.8 Hz, 2H), 4.08 (t,J=4.95 Hz, 2H), 3.74 (m, 3H), 3.28-3.21 (m, 2H), 2.72-2.61 (m, 2H),2.40-2.20 (m, 6H), 2.05-1.91 (m, 3H).

2.10. Synthesis ofN-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-2-(isoquinolin-5-yl)acetamide(51)

The title compound was prepared from 2-(isoquinolin-5-yl)acetic acid and3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-amine using Protocol Bexcept that triethylamine was also added. MS(ESI) 416.0 [M+H], Retentiontime=2.86 min; ¹H-NMR (300 MHz, CDCl₃): δ 9.40 (s, 1H), 8.57 (d, J=6.04Hz, 1H), 8.10-8.07 (m, 2H), 8.0 (d, J=6.6 Hz, 1H), 7.90-7.88 (m, 1H),7.83-7.77 (m, 1H), 7.71-7.68 (m, 1H), 7.55-7.51 (m, 1H), 7.42-7.37 (m,1H), 6.56 (s, 1H), 4.39 (s, 2H), 2.56 (s, 3H).

2.11. Synthesis ofN-(4-cyano-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

2.11.1. (E)-Ethyl 3-(2-amino-5-(trifluoromethyl)phenyl)acrylate

To a mixture of 2-bromo-4-(trifluoromethyl)aniline (5 g, 20.83 mmol),triethylamine (4.4 mL, 31.2 mmol) and P(o-tol)₃ (2.5 g, 8.33 mmol) inDMF (42 mL, 0.5 M) in a glass pressure tube under nitrogen gas wereadded ethyl acrylate (2.3 g, 23 mmol) and palladium acetate (940 mg,4.167 mmol). The tube was sealed and heated to 120° C. for 18 h. Theresulting solution was concentrated under vacuum and purified by columnchromatography. Retention time (min)=2.532, method [1], MS(ESI) 260.1(M+H).

2.11.2. 6-(Trifluoromethyl)quinolin-2(1H)-one

To a stirring mixture of (E)-ethyl3-(2-amino-5-(trifluoromethyl)phenyl)acrylate (4 g, 15.4 mmol) in 4N HClin dioxane (20 mL) was added concentrated HCl (3 mL). The resultingmixture was warmed to 100° C. overnight. The reaction mixture was cooledto rt and then slowly quenched with a cold saturated NaHCO₃ solutionuntil pH>7. A normal aqueous extraction with EtOAc was followed. Thecrude mixture was taken directly to the next reaction without furtherpurification. Retention time (min)=1.849, method [1], MS(ESI) 214.0(M+H).

2.11.3. Ethyl 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetate

To a stirring mixture of the above crude6-(trifluoromethyl)quinolin-2(1H)-one in DMF/THF (0.5 M, 1:1) at rt wasadded NaH portionwise (1.2 g, 30.88 mmol) over 15 min. The reactionmixture was stirred at rt for additional 20 min before a solution ofbromo methyl acetate (4.73 g, 30.88 mmol) in THF was added. Theresulting mixture was stirred at rt until the starting material wasconsumed. The mixture was slowly quenched with brine and extracted withEtOAc. The crude product mixture was purified by column chromatography(3.6 g, 82% in two steps). Retention time (min)=2.042, method [1],MS(ESI) 286.1 (M+H).

2.11.4. 2-(2-Oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid

To a stirring solution of methyl2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetate (4.8 g, 16.8 mmol)in THF/water (25 mL/5 mL, 5:1) was added LiOH.H₂O (3.52 g, 84.2 mmol).The resulting mixture was stirred overnight. The crude mixture wasslowly acidified with 1N HCl and then extracted with EtOAc. The organicphase was dried (MgSO₄), filtered and concentrated under vacuum to give2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (4.3 g).Retention time (min)=3.005, method [7], MS(ESI) 272.1 (M+H).

2.11.5. 5-Nitro-4-(thiazol-2-yl)thiophene-3-carbonitrile

A mixture of 4-bromo-5-nitrothiophene-3-carbonitrile (0.5 g, 2.1 mmol),2-(tributylstannyl)thiazole (1.2 g, 3.2 mmol), dioxane (3.5 mL), andtetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.21 mmol) was heatedby microwave to 130° C. for 30 min under nitrogen. The reaction mix wasconcentrated under reduced pressure, and the resulting dark oil waspurified by column chromatography using a mobile phase of 20%EtOAc/hexanes to give 5-nitro-4-(thiazol-2-yl)thiophene-3-carbonitrile(180 mg) as an oil. LCMS of this material revealed an m/z of 238.0 witha retention time of 1.807 min method [1].

2.11.6. 5-Amino-4-(thiazol-2-yl)thiophene-3-carbon

A 30mL reaction vial was charged with5-nitro-4-(thiazol-2-yl)thiophene-3-carbonitrile (180 mg, 0.76 mmol) andAcOH (3mL). A spatula tip of iron dust was added and the reaction vialwas heated to 60° C. for 20 min. The reaction mixture was cooled to 23°C. and partitioned between methylene chloride and sodium bicarbonatesolution. The organic solution was dried over sodium sulfate andconcentrated to give 5-amino-4-(thiazol-2-yl)thiophene-3-carbonitrile asa red solid. LCMS showed an m/z of 208.0 with a retention time of 2.016min using method [1].

2.11.7.N-(4-Cyano-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-acetamide

The title compound was prepared from5-amino-4-(thiazol-2-yl)thiophene-3-carbonitrile (271 mg, 1 mmol) and2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.76 mmol)according to protocol A. The crude product was purified by columnchromatography (35% EtOAc/hexanes) and HPLC to giveN-(4-cyano-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide(24 mg) as a white solid with an m/z of 461.1 and retention of 7.348 minusing the [7] LCMS method. ¹H-NMR (300 MHz, CDCl₃): δ 13.21 (s, 1H),7.93 (m, 2H), 7.86 (dd, J=8.9, 1.8 Hz, 1H), 7.58 (s, 1H), 7.54 (d, J=3.4Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.31 (d, J=3.3 Hz, 1H), 7.00 (d, J=9.6Hz, 1H), 5.35 (s, 2H). ¹³C-NMR (75 MHz, CDCl₃): δ 165.3, 161.7, 161.0,140.8, 140.0, 139.9, 129.4, 129.0, 128.0, 126.5, 122.7, 120.4, 117.8,115.9, 115.0, 114.7, 106.0, 46.3.

2.12. Synthesis ofN-(4-cyano-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

The title compound was prepared from5-amino-4-(thiazol-2-yl)thiophene-3-carbonitrile (67 mg, 0.32 mmol) and2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (100 mg, 0.48mmol) according to protocol A. The crude product was purified by columnchromatography (2% methanol/methylene chloride) and HPLC to giveN-(4-cyano-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihdyro-1,5-naphthyridin-1(2H)-yl)acetamide(5.4 mg) as a white solid. LCMS m/z 396.1, method [7]retention time2.611 min. ¹H-NMR (300 MHz, CDCl₃): δ 8.39 (d, J=4.1 Ha, 1H), 7.76 (d,J=3.3 Hz, 2H), 7.62 (s, 1H), 7.58 (d, J=7.4 Hz, 1H), 7.44 (m, 2H), 3.46(t, J=7.1 Hz, 2H), 3.02 (t, J=7.2 Hz, 2H).

Synthesis ofN-(4-bromo-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

2.13.1. 2-(4-Bromo-2-nitrothiophen-3-yl)thiazole

A mixture of 3,4-dibromo-2-nitrothiophene (242 mg, 0.85 mmol),2-(tributylstannyl)thiazole (315 mg, 0.84 mmol), Pd(Ph₃P)₄ catalyst (194mg, 0.17 mmol) and dioxane (0.9 mL) was heated in the microwave to 130°C. for 25 min. The reaction mixture was diluted with EtOAc and filteredto remove solids. The remaining organic solution was washed withsaturated, aqueous solutions of sodium bicarbonate and salt beforedrying over sodium sulfate. The organic was concentrated under reducedpressure to give a dark oil. The crude product was purified by columnchromatography (30% EtOAc/hexanes) to give2-(4-bromo-2-nitrothiophen-3-yl)thiazole (210 mg). LCMS m/z of289.1/291.1 with a retention time of 2.043 min on the [1] method.

2.13.2. 4-Bromo-3-(thiazol-2-yl)thiophen-2-amine

The title compound was prepared from2-(4-bromo-2-nitrothiophen-3-yl)thiazole (120 mg, 0.41 mmol) accordingto the procedures of Example 2.11.6 to give4-bromo-3-(thiazol-2-yl)thiophen-2-amine as a dark residue (90 mg). LCMSm/z of 260.9/292.9 with a retention time of 6.003 min in the [7] method.

2.13.3.N-(4-Bromo-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

The title compound was prepared from4-bromo-3-(thiazol-2-yl)thiophen-2-amine (90 mg, 0.35 mmol) and2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (105 mg, 0.52mmol) according to protocol A. The crude product was purified by HPLC togiveN-(4-bromo-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide(24 mg) as a white solid. LCMS m/z 449.0/451.0 and retention of 4.019min using method [7]. ¹H-NMR (300 MHz, CDCl₃) δ 8.39 (d, J=5.2Hz, 1H),7.76 (d, J=3.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.51 (dd, J=8.4, 5.3 Hz,1H), 7.34 (d, J=3.4, 1H), 6.94 (s, 1H), 4.09 (s, 2H), 3.49 (t, J=7.2,Hz, 2H), 3.00 (t, J=7.2 Hz, 2H).

2.14. Synthesis ofN-(4-chloro-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

2.14.1. 2-(4-Chloro-2-nitrothiophen-3-yl)thiazole

A mixture of 2-(4-bromo-2-nitrothiophen-3-yl)thiazole (120 mg, 0.41mmol), CuCl (240 mg) in dioxane (1.5 mL) and 5 drops of DMF was heatedto 110° C. for 1h by microwave. The reaction mixture was diluted withEtOAc and washed with saturated, aqueous sodium bicarbonate and brinebefore drying over sodium sulfate. It was concentrated under reducedpressure to give 2-(4-chloro-2-nitrothiophen-3-yl)thiazole as a yellowresidue (100 mg). LCMS m/z of 246.9/249.0 with a retention time of 3.994min on the [7] method.

2.14.2. 4-Chloro-3-(thiazol-2-yl)thiophen-2-amine

The title compound was prepared from2-(4-chloro-2-nitrothiophen-3-yl)thiazole (100 mg, 0.4 mmol) accordingto the procedures of Example 2.11.6 to give4-chloro-3-(thiazol-2yl)thiophen-2-amine as a dark residue (90 mg). LCMSm/z of 217.0/218.9 with a retention time of 2.426 min in the [1] method.

2.14.3.N-(4-Chloro-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

The title compound was prepared from4-chloro-3-(thiazol-2-yl)thiophen-2-amine (0.4 mmol) and2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (165 mg, 0.8mmol) according to protocol A. The crude product was purified by columnchromatography (4% methanol/methylene chloride) and HPLC to affordN-(4-chloro-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide(2.1 mg) as a white solid. LCMS m/z of 405.1/407.1 and retention of3.670 min using the [7] LCMS method. ¹H-NMR (300 MHz, CDCl₃): δ 8.36 (d,J=4.9 Hz, 1H), 7.71 (d, J=3.4 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.42 (dd,J=8.1, 5.1 Hz, 1H), 7.36 (d, J=3.4, 1H), 6.82 (s, 1H), 4.92 (s, 2H),3.44 (t, J=7.1 Hz, 2H), 3.01 (t, J=7.1 Hz, 2H).

2.15. Synthesis ofN-(4-chloro-3-(thiazol-2-yl)thiophen-2-yl)-2-(8-(trifluoromethyl)quinolin-5-yl)acetamide

The title compound was prepared from4-chloro-3-(1H-1,2,4,-triazol-5-yl)thiophen-2-amine (150 mg, 0.75 mmol)and 2-(8-(trifluoromethyl)quinolin-5-yl)acetic acid (148 mg, 0.58 mmol)according to protocol A. The crude product was purified by columnchromatography (35% EtOAc/hexanes) to giveN-(4-chloro-3-(thiazol-2-yl)thiophen-2-yl)-2-(8-(trifluoromethyl)quinolin-5-yl)acetamide(35 mg) as a white solid. LCMS m/z of 438.1/440.1 and retention of 5.789min using the [7] LCMS method. ¹H-NMR (300 MHz, DMSO-d₆): δ 9.06 (dd,J=4.2, 1.6 Hz, 1H), 8.64 (dd, J=8.7, 1.6 Hz, 1H), 8.26 (d, J=7.6 Hz,1H), 7.83 (d, J=7.5 Hz, 1H), 7.72 (dd, J=8.6, 4.2 Hz, 1H), 7.13 (s, 1H),4.56 (s, 2H).

2.16. Synthesis ofN-(4-cyano-3-(thiazol-4-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

2.16.1. 5-Nitro-4-(thiazol-4-yl)thiophen-3-carbonitrile

A microwave vial equipped with a stir bar was added4-bromo-5-nitrothiophene-3-carbonitrile (0.15 g, 0.66 mmole) andtetrakis(triphenylphosphine)palladium(0) (0.077 g, 0.066 mmol) and thenpurged with N₂ (g) inlet prior to addition of4-(tributylstannyl)thiazole (0.42 g, 1.13 mmol), dioxane (1.2 mL) andfew drops of DMF. The reaction mixture was heated at 110° C. for 30 minand then concentrated under reduced pressure. Purification by flashchromatography (silica, 50:50 ethyl acetate/hexane) gave5-nitro-4-(thiazol-4-yl)thiophene-3-carbonitrile (71 mgs, 45) Retentiontime (min)=1.656, method [4], MS(ESI) 238.0 (M+H).

2.16.2. 5-amino-4-(thiazol-4-yl)thiophene-3-carbonitrile Protocol Q

To a solution of 5-nitro-4-(thiazol-4-yl)thiophene-3-carbonitrile (0.071g, 0.31 mmol) in ethyl acetate (3 mL) was added tin (II) chloridedihydrate (0.29 g, 1.27 mmol). The reaction mixture was heated in an oilbath set at 70° C. under condenser. After 20 min. the mixture was cooledto RT and concentrated under reduced pressure. Purification by flashchromatography (silica, 40:60 ethyl acetate/hexane) gave5-amino-4-(thiazol-4-yl)thiophene-3-carbonitrile (24 mgs, 38%) Retentiontime (min)=1.837, method [4], MS(ESI) 208.0 (M+H).

2.16.3.N-(4-Cyano-3-(thiazol-4-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)yl)acetamide

The title compound was prepared from2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.047 g, 0.17mmol) and 5-amino-4-(thiazol-4-yl)thiophene-3-carbonitrile (0.024 g,0.12 mmol) according to protocol A. The desired product was submitted toprep HPLC for further purification. Retention time (min)=7.57, method[7], MS(ESI) 461.1 (M+H). ¹H NMR (300 MHz, CDCl₃): δ 12.73 (s, 1H), 8.60(d, J=2.4 Hz, 1H), 8.14 (d, J=2.4 Hz, 1H), 7.92-7.89 (m, 2H), 7.89 (d,J=9.3 Hz, 1H), 7.59 (s, 1H), 7.49 (d, J=8.9 Hz, 1H), 6.96 (d, J=9.3 Hz,1H), 5.30 (s, 2H).

2.17. Synthesis ofN-(4-cyano-3-(thiazol-5-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

2.17.1. 5-Nitro-4-(thiazol-5-yl)thiophene-3-carbonitrile Protocol R

A microwave vial equipped with a stir bar was added4-bromo-5-nitrothiophene-3-carbonitrile (0.24 g, 1.05 mmole) andtetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmol), copperiodide (0.028 g, 0.15 mmol) and then purged with N₂ (g) inlet prior toaddition of 5-(tributylstannyl)thiazole (0.63 g, 1.67 mmol), dioxane(2.3 mL) and few drops of DMF. The reaction mixture was heated at 110°C. for 30 min and then concentrated under reduced pressure. Purificationby flash chromatography (silica, 40:60 ethyl acetate/hexane) gave5-nitro-4-(thiazol-5-yl)thiophene-3-carbonitrile (153 mgs, 61%)Retention time (min)=1.715, method [4], MS(ESI) 238.0 (M+H).

2.17.2. 5-Amino-4-(thiazol-5-yl)thiophene-3-carbonitrile

5-Amino-4-(thiazol-5-yl)thiophene-3-carbonitrile was prepared from5-nitro-4-(thiazol-5-yl)thiophene-3-carbonitrile (0.15 g, 0.65 mmol)according to protocol Q. Retention time (min)=1.520, method [7], MS(ESI)208.0 (M+H).

2.17.3.N-(4-Cyano-3-(thiazol-5-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.047 g, 0.17mmol) and 5-amino-4-(thiazol-5-yl)thiophene-3-carbonitrile (0.055, 0.26mmol) according to protocol A. The crude product was purified by prepHPLC. Retention time (min)=5.989, method [7], MS(ESI) 451.1 (M+H). ¹HNMR (300 MHz, CDCl₃): δ 9.95 (s, 1H), 7.91-7.85 (m, 4H) 7.78 (d, J=8.7Hz, 1H), 7.63 (s, 1H), 6.84 (d, J=8.7 Hz, 1H), 5.06 (s, 2H).

2.18 Synthesis ofN-(3-benzo[d]thiazol-2-yl)-4-cyanothiophen-2-yl)-2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetamide

2.18.1. 5-Nitro-4-(benzo[d]thiazol-2-yl)thiophene-3-carbonitrile

5-nitro-4-(benzo[d]thiazol-2-yl)thiophene-3-carbonitrile was preparedfrom 4-bromo-5-nitrothiophene-3-carbonitrile (0.16 g, 0.67 mmol) and2-(tributylstannyl)benzo[d]thiazole (0.45 g, 1.07 mmol) according toprotocol R. Retention time (min)=0.381, method [4], MS(ESI) 288.0 (M+H).

2.18.2. 5-Amino-4-(benzo[d]thiazol-2-yl)thiophene-3-carbonitrile

5-amino-4-(benzo[d]thiazol-2-yl)thiophene-3-carbonitrile was preparedfrom 5-nitro-4-(benzo[d]thiazol-2-yl)thiophene-3-carbonitrile (0.27 g,0.92 mmol) according to protocol Q. Retention time (min)=2.579, method[4], MS(ESI) 258.0 (M+H).

2.18.3.N-(3-benzo[d]thiazol-2-yl)-4-cyanothiophen-2-yl)-2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetic acid (0.040 g, 0.19 mmol) and5-amino-4-(benzo[d]thiazol-2-yl)thiophene-3-carbonitrile (0.073 g, 0.28mmol) according to protocol A. The crude product was purified by prepHPLC. LCMS retention time (min)=5.122, method [12], MS(ESI) 446.1 (M+H).¹H NMR (CDCl₃): δ 13.38 (s, 1H), 8.32 (d, J=5.6 Hz, 1H), 7.99 (d, J=7.5Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=8.4 Hz, 1H),7.54 (d, J=8.4 Hz, 1H), 7.47-7.42 (m, 1H), 7.35-7.30 (m, 1H), 4.95 (s,2H), 3.33-3.28 (m, 2H), 2.99-2.94 (m, 2H).

2.19. Synthesis of2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)-N-(2-(thiazol-4-yl)thiophen-3-yl)acetamide

The title compound was prepared from 2-(thiazol-4-yl)thiophen-3-amineand 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid accordingto protocol A. Retention time (min)=6.485, method [7], MS(ESI) 436.1(M+H). ¹H NMR (300 MHz, CD₃Cl): δ 11.32 (s, 1H), 8.51 (d, J=1.5 Hz, 1H),8.04 (d, J=5.5 Hz, 1H), 7.92 (d, J=10.2 Hz, 1H), 7.90 (s, 1H), 7.80 (d,J=8.9 Hz, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.22 (d, J=1.4 Hz, 1H), 7.20 (d,J=5.5 Hz, 1H), 7.03 (d, J=9.7 hz, 1H), 5.23 (s, 2H).

EXAMPLE 3 Synthesis of Thiophene Oxazoles 3.1. Synthesis of2-(4-methoxyphenyl)-N-(2-(oxazol-2-yl)thiophen-3-yl)acetamide (52)

3.1.1. 2-(3-Nitrothiophen-2-yl)oxazole

2-(3-nitrothiophen-2-yl)oxazole was prepared from2-tributylstannyl)oxazole (0.94 g, 2.62 mmol) and2-chloro-3-nitrothiophene (0.429 g, 2.62 mmol) according to protocol E.Retention time (min)=1.794, method [1], MS(ESI) 197.0 (M+H).

3.1.2. 2-(Oxazol-2-yl)thiophen-3-amine

2-(Oxazol-2-yl)thiophen-3-amine was prepared from2-(3-nitrothiophen-2-yl)oxazole (250 mg, 1.27 mmol) according toprotocol F. Retention time (min)=1.388, method [1], MS(ESI) 167.0 (M+H).

3.1.3. 2-(4-Methoxyphenyl)-N-(2-(oxazol-2-yl)thiophen-3-yl)acetamide

2-(4-methoxyphenyl)-N-(2-(oxazol-2-yl)thiophen-3-yl)acetamide wasprepared from 2-(4-methoxyphenyl)acetic acid 64 mg, 0.385 mmol) and2-(oxazol-2-yl)thiophen-3-amine (64 mg, 0.385 mmol) according toprotocol A. Retention time (min)=6.845, method [7], MS(ESI) 315.1 (M+H);¹H NMR (300 MHz, CDCl₃): δ 10.59 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.52(s, 1H), 7.28-7.37 (m, 3H), 6.94-6.99 (m, 3H), 3.85 (s, 3H), 3.66 (s,2H).

3.2. Synthesis of2-(isoquinolin-5-yl)-N-(2-(oxazol-2-yl)thiophen-3-yl)acetamide (53)

2-(Isoquinolin-5-yl)-N-(2-(oxazol-2-yl)thiophen-3-yl)acetamide wasprepared from 2-(isoquinolin-5-yl)acetic acid (48 mg, 0.246 mmol) and2-(oxazol-2-yl)thiophen-3-amine (41 mg, 0.246 mmol) according toprotocol A. Retention time (min)=2.206, method [7], MS(ESI) 336.1 (M+H);¹H NMR (300 MHz, CDCl₃): δ 10.79 (s, 1H), 9.71 (s, 1H), 8.59 (d, J=6.5Hz, 1H), 8.36 (d, J=6.5 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.07-8.13 (m,2H), 7.95 (dd, J=8.3, 7.3 Hz, 1H), 7.55 (s, 1H), 7.36 (d, J=5.3 Hz, 1H),6.95 (s, 1H), 4.36 (s, 2H).

3.3. Synthesis ofN-(4-bromo-3-(oxazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

3.3.1. 2-(4-Bromo-2-nitrothiophen-3-yl)oxazole

A mixture of 3,4-dibromo-2-nitrothiophene (0.166 mg, 0.581 mmol),Pd(PPh₃)₄ (67 mg, 0.0581 mmol) and 2-(tributylstannyl)oxazole (250 mg,0.698 mmol) n DMF (1.1 mL) was evacuated and purged with nitrogen threetimes. The reaction mixture was heated to 90° C. for 18 h and theresulting solution was cooled to room temperature and diluted with Et₂O.The solution was washed with brine and the organic phase was separated,dried (Na₂SO₄), filtered, concentrated under vacuum and purified on asilica gel column (eluant hexane/ethyl acetate, 20/1 to 1/1, v/v) togive 2-(4-bromo-2-nitrothiophen-3-yl)oxazole (107 mg, 67%). Retentiontime (min)=1.948, method [1], MS(ESI) 274.9 (M+H).

3.3.2. 4-Bromo-3-(oxazol-2-yl)thiophen-2-amine

The title compound was prepared from2-(4-bromo-2-nitrothiophen-3-yl)oxazole (224 mg, 0.814 mmol) using theprocedures of Example 2.11.6 to give4-bromo-3-(oxazol-2-yl)thiophen-2-amine which was used without furtherpurification. Retention time (min)=2.131, method [1], MS(ESI) 244.9(M+H).

3.3.3.N-(4-Bromo-3-(oxazol-2-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (85 mg, 0.416mmol) and 4-bromo-3-(oxazol-2-yl)thiophen-2-amine (51 mg, 0.208) mmol)according to protocol A. Retention time (min)=3.245, method [7], MS(ESI)433.0 (M+H); ¹H NMR (300 MHz, CDCl₃): δ 8.39 (dd, J=5.1, 1.0 Hz, 1H),7.72 (s, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.45 (dd, J=8.4, 5.5 Hz, 1H), 7.17(s, 1H), 6.94 (s, 1H), 4.93 (s, 2H), 3.51-3.46 (m, 2H), 3.05-3.00 (m,2H).

3.4. Synthesis ofN-(4-cyano-3-(oxazol-2-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

3.4.1. 5-Nitro-4-(oxazol-2-yl)thiophene-3-carbonitrile

The above titled compound (34 mg, 18%) was synthesized from4-bromo-5-nitrothiophene-3-carbonitrile (203 mg, 0.87 mmol) and2-tributylstannyloxazole (0.27 mL, 1.29 mmol),tetrakis(triphenylphosphine)palladium(0) (103 mg, 0.089 mmol) andcopper(I) iodide (16 mg, 0.084 mmol) according to methods describedherein. LCMS method [4], retention time=1.62 min; MS(ESI) 222.0 (MH+).

3.4.2. 5-Amino-4-(oxazol-2-yl)thiophene-3-carbonitrile

The title compound was prepared from5-nitro-4-(oxazol-2-yl)thiophene-3-carbonitrile (34 mg, 0.15 mmol) usingprotocol Q. Flash chromatography (EtOAc/hexanes elution) gave desiredproduct (20.8 mg, 71%): R_(f)=0.84 (60% EtOAc/hexanes, silica); HPLCmethod [4], retention time =1.673 min; MS(ESI) 192.0 (MH+).

3.4.3.N-(4-Cyano-3-(oxazol-2-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide

The title compound was synthesized from5-amino-4-(oxazol-2-yl)thiophene-3-carbonitrile (21 mg, 0.11 mmol) and2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (30 mg, 0.11mmol) according to protocol A. The product was purified by HPLC. LCMSmethod [7], retention time=6.70 min; MS(ESI) 445.0 (MH+); ¹H NMR (300MHz, CD₃OD): δ 8.19 (d, J=9.8 Hz, 2H), 7.95-7.80 (m, 3H), 7.85 (d, J=1.8Hz, 1H), 7.08 (d, J=0.8 Hz, 1H), 6.90 (d, J=9.6 Hz, 1H), 5.45 (s, 2H).

EXAMPLE 4 Synthesis of Thiophene Oxadiazoles 4.1 Synthesis of2-(4-methoxyphenyl)-N-(3-(5-methyl-1,2,4-oxadiazol-3-yl)thiophen-2-yl)acetamide(54)

4.1.1. 4-(3-Cyanothiophen-2-)-2-(4-methoxyphenyl)acetamide

N-(3-cyanothiophen-2-l)-2-(4-methoxyphenyl)acetamide was prepared from2-(4-methoxyphenyl)acetic acid (1.37 g, 8.29 mmol) and2-aminothiophene-3-carbonitrile (1.03 g, 8.29 mmol) according toprotocol B. Retention time (min)=2.150, method [1], MS(ESI) 273.0 (M+H).

4.1.2.N-(3-(N′-Hydroxycarbaminidoyl)thiophen-2-yl)-2-(4-methoxyphenyl)-acetamide

To a solution of N-(3-cyanothiophen-2-yl)-2-(4-methoxyphenyl)acetamide(234 mg, 0.859 mmol) in a mixture of ethanol (5 mL), methylene chloride(0.5 mL) and triethylamine (202 μL, 1.46 mmol) was added hydroxylaminehydrochloride (90 mg, 1.29 mmol). The resulting solution was stirred atroom temperature for 18 h and was subsequently diluted with saturatedaqueous sodium bicarbonate and extracted with ethyl acetate. The organicphases were combined, dried (Na₂SO₄), filtered, concentrated undervacuum and purified on a silica gel column (eluant hexane/ethyl acetate,7/3 to 2/8) to giveN-(3-(N′-hydroxycarbamimidoyl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide.Retention time (min)=1.161, method [1], MS(ESI) 306.1 (M+H).

4.1.3.2-(4-Methoxyphenyl)-N-(3-(5-methyl-1,2,4-oxadiazol-3-yl)thiophen-2-yl)acetamide

To a solution ofN-(3-(N′-hydroxycarbamimidoyl)thiophen-2-yl)-2-(4-methoxyphenyl)-acetamide(104 mg, 0.341 mmol) in acetonitrile (2 mL) was added DIPEA (127 mg,0.987 mmol) and acetyl chloride (48 μL, 0.681 mmol). The resultingsolution was stirred at 60° C. for 18 h and was subsequently dilutedwith saturated aqueous sodium bicarbonate and extracted with ethylacetate. The organic phases were combined, dried (Na₂SO₄), filtered,concentrated under vacuum and purified by preparative HPLC to give2-(4-methoxyphenyl)-N-(3-(5-methyl-1,2,4-oxadiazol-3-yl)thiophen-2-yl)acetamide.Retention time (min)=6.733, method [7], MS(ESI) 330.1 (M+H); ¹H NMR (300MHz, CDCl₃): δ 10.63 (s, 1H), 7.30-7.35 (m, 3H), 7.00 (d, J=9.2 Hz, 2H),6.89 (d, J=6.2 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 2H), 2.50 (s, 3H).

4.2 Synthesis ofN-(2-(1,3,4-oxadiazol-2-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(55)

To a solution of (isocyanoimino)triphenylphosphorane (978 mg, 3.24 mmol)in anhydrous CH₂Cl₂ (30 mL) was added dropwise a solution of3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylic acid (340 mg,1.09 mmol) in anhydrous CH₂Cl₂ (27 mL). The resulting mixture wasstirred at room temperature under nitrogen overnight and evaporatedunder reduced pressure. Purification by flash chromatography (silica,30:70 ethyl acetate/hexane) gaveN-(2-(1,3,4-oxadiazol-2-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(45 mg, 12%). Method [7] m/z 357.9 (M+Na); retention time=5.919. ¹H-NMR(CDCl₃): δ 8.18 (d, J=1.1 Hz, 1H), 8.16 (d, J=1.4 Hz, 1H), 8.05 (d,J=8.3 Hz, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.61-7.41 (m, 5H), 4.27 (s, 2H).

4.3. Synthesis of2-(4-methoxyphenyl)-N-(2-(5-methyl-1,3,4-oxadiazol-2-yl)thiophen-3-yl)acetamide(56)

4.3.1. Methyl 3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylate

The title compound was prepared from 4-methoxyphenyl acetic acid (6.65g, 40.2 mmol) and methyl-3-amino-2-thiophene carboxylate (6.30 g, 40.08mmol) using protocol A to afford the coupled intermediate (7.40 g, 60%).Method [7] m/z 306.0 (M+H); retention time=5.907. ¹H-NMR (300 MHz,CDCl₃): δ 10.04, (broad s, 1H), 8.07 (d, J=5.5 Hz, 1H), 7.38 (d, J=5.5Hz, 1H), 7.22 (d, J=8.3 Hz, 2H,), 6.88 (d, J=8.3 Hz, 2H), 3.76 (s, 3H),3.75 (s, 3H), 3.65 (s, 2H).

4.3.2. 3-(2-(4-Methoxyphenyl)thiophene-2-carboxylic acid

A 3M lithium hydroxide solution (80 mL) was added tomethyl-3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylate (7.30 g,23.91 mmol) dissolved in methanol. The reaction mixture was refluxed for2 h, cooled to room temperature and then partitioned between ethylacetate and H₂O. The aqueous layer with acidified with conc HCl,filtered and washed with H₂O. The precipitate that formed was collectedby filtration (8.55 g, quantitative) and used in the next step withoutfurther purification. Method [7] m/z 291.9 (M+H); retention time=3.827.¹H-NMR (CD₃OD): δ 8.0 (d, J=5.3 Hz, 1H), 7.61 (d, J=5.3 Hz, 1H), 7.26(d, J=8.3 Hz, 2H), 6.91 (d, J=8.3 Hz, 2H), 3.76 (s, 3H), 3.70 (s, 2H).

4.3.3.N-(2-(2-Acetylhydrazinecarbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)-acetamide

the title compound was prepared from3-(2-(4-methoxyphenyl)acetamido)-thiophene-2-carboxylic acid (500 mg,1.72 mmol) and acetylhydrazide (1.0 g, 13.50 mmol) according to protocolB to giveN-(2-(2-acetylhydrazinecarbonyl)thiophene-3-yl)-2-(4-methoxyphenyl)acetamidewhich was used without further purification (300 mg, 50%). Method [4]m/z 370.0 (M+Na); retention time=1.186.

4.3.4.2-(4-Methoxyphenyl)-N-(2-(5-methyl-1,3,4-oxadiazol-2-yl)thiophen-3-yl)acetamide

To a solution ofN-(2-(2-acetylhydrazinecarbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(300 mg, 0.86 mmol) in anh. acetonitrile (6 mL) was addeddiisopropylethylamine (0.8 mL, 4.84 mmol) and triphenylphosphine (396mg, 1.51 mmol). After 5 min, hexachloroethane (292 mg, 1.23 mmol) wasadded to the reaction mixture and then stirred at room temperatureovernight under N₂ (g) inlet. The reaction mixture was evaporated underreduced pressure, partitioned between ethyl acetate and H₂O, dried(sodium sulfate), filtered and concentrated under reduced pressure.Purification by flash column chromatography (silica, 40:60 ethylacetate/hexane) gave2-(4-methoxyphenyl)-N-(2-(5-methyl-1,3,4-oxadiazol-2-yl)thiophen-3-yl)acetamide(25 mg, 9%). See James, C. A. et al., Tet. Lett. 47 (2006) 511-514.Method [7] m/z 330.0 (M+H); retention time=4.805. ¹H-NMR (CDCl₃): δ10.15 (broad s, 1H), 8.18 (d, J=5.4 Hz, 1H). 7.43 (d, J=5.4 Hz, 1H),7.31 (d, J=7.6 Hz, 2H), 6.92 (d, J=7.6 Hz, 2H), 3.81 (s, 3H), 3.75 (s,2H), 2.75 (s, 3H).

4.4. Synthesis ofN-(2-(5-isopropyl-1,3,4-oxadiazol-2-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(57)

4.4.1.N-(2-(2-Isobutyrylhydrazinecarbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)-acetamide

N-(2-(2-isobutyrylhydrazinecarbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(443 mg, 34%) was prepared from3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylic acid andisobutyrohydrazine according to essentially the same procedure asdescribed above in Example 4.3.3. and was purified by flash columnchromatography (silica, 50:50 ethyl acetate/hexane). Method [4]m/z 398.0(M+Na); retention time=1.453.

4.4.2.N-(2-(5-Isopropyl-1,3,4-oxadiazol-2-yl)thiophen-3-yl)-2-(4-methoxyphenyl)-acetamide

N-(2-(5-isopropyl-1,3,4-oxadiazol-2-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide(339 mgs, 81%) was prepared fromN-(2-(2-isobutyrylhydrazinecarbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamideaccording to essentially the same procedure as described for Example4.3.4 and was purified by flash column chromatography (silica, 50:50ethyl acetate/hexane). Method [7] m/z 358.0 (M+H); retention time=6.683.¹H-NMR (CDCl₃): δ 10.21 (broad s, 1H), 8.15 (d, J=5.2 Hz, 1H), 7.40 (d,J=5.2 Hz, 1H), 7.29 (d, J=8.2 Hz, 2H), 6.89 (d, J=8.2 Hz, 2H), 3.79 (s,3H), 3.71 (s, 2H), 3.24-3.14 (m, 1H). 1.42 (s, 3H). 1.40 (s, 3H).

4.5. Synthesis ofN-(2-(5-methyl-1,3,4-oxadiazol-2-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(58)

4.5.1.N-(2-(2-Acetylhydrazinecarbonyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide

The title compound was prepared from3-(2-(naphthalene-1-yl)acetamido)thiophene-2-carboxylic acid (321 mg,1.03 mmol) and methyl keto hydrazine (609 mg, 8.22 mmol) using protocolB to give the desiredN-(2-(2-acetylhydrazinecarbonyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide,which was used without further purification (250 mg, 66%).

4.5.2.N-(2-(5-Methyl-1,3,4-oxadiazol-2-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide

N-(2-(5-methyl-1,3,4-oxadiazol-2-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(105 mgs, 44%) was prepared fromN-(2-(2-acetylhydrazinecarbonyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(250 mg, 0.68 mmol) according to essentially the same procedure asdescribed in Example 4.3.4. Method [7] m/z 371.9 (M+Na); retentiontime=6.243. ¹H-NMR (CDCl₃): δ 10.08 (s, 1H), 8.12 (d, J=5.4 Hz, 1H),8.03 (d, J=8.1 Hz, 1H), 7.83 (d, J=8.1 HZ, 2H), 7.57-7.40 (m, 4H), 7.33(d, J=5.4 Hz, 1H), 4.21 (s, 2H), 2.45 (s, 3H).

4.6. Synthesis ofN-(4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2-(naphthalen-1-yl)acetamide(59)

4.6.1. Methyl4-methyl-2-(2-(naphthalen-1-yl)acetamido)thiophene-3-carboxylate

The title compound was prepared from 2-(naphthalen-1-yl)acetic acid (10g, 54 mmol) and methyl 2-amino-4-methylthiophene-3-carboxylate (9.2 g,54 mmol) according to protocol A (15.4 g, 85%) as a white solid. ¹H NMR(CDCl₃): δ 11.0 (s, 1H), 8.05-7.85 (m, 3H), 7.63-7.50 (m, 4H), 6.36 (s,1H), 4.29 (s, 2H), 3.57 (s, 3H), 2.28 (s, 3H); ¹³C NMR (CDCl₃): δ 168.3,165.6, 149.3, 135.0, 134.0, 132.1, 129.8, 128.9, 128.6, 127.0, 126.2,125.7, 123.7, 112.9, 112.2, 51.1, 41.9, 17.7; MH+ 340.

4.6.2.N-(4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2-(naphthalen-1-yl)acetamide

Sodium hydride (60% dispersion in mineral oil, 106 mg, 2.65 mmol) wasadded to a solution of acetamide oxime (218 mg, 2.94 mmol) in dry THF (5mL) at rt. Methyl4-methyl-2-(2-(naphthalen-1-yl)acetamido)thiophene-3-carboxylate(Aldrich, 500 mg, 1.47 mmol) was added, and the reaction mixture wasallowed to stir over 3 days. The mixture was concentrated under reducedpressure, then partitioned between ethyl acetate and water. The organiclayer was separated, and washed with saturated NaCl solution. Theorganic layer was dried (MgSO₄), filtered and concentrated. The residuewas purified by flash chromatography(EtOAc/hexanes elution), and thentriturated from acetonitrile to afford the desired product (58 mg) as awhite solid. Method [7]: rt=9.42 min; ¹H NMR (CDCl₃): δ 11.13 (s, 1H),8.02-7.89 (m, 3H), 7.63-7.50 (m, 4H), 6.48 (s, 1H), 4.35 (s, 2H), 2.42(s, 3H), 2.08 (s, 3H); ¹³C NMR (CDCl₃): δ 172.1, 168.9, 165.2, 146.4,134.0, 133.4, 132.4, 129.4, 129.1, 129.0, 128.8, 127.2, 126.4, 125.7,123.7, 114.0, 106.9, 42.1, 16.9, 11.4; MH+ 364.1.

4.7 Synthesis ofN-(4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2-(4-(pyridin-4-yl)phenyl)acetamide(60)

4.7.1. Methyl2-(2-(4-iodophenyl)acetamido)-4-methylthiophene-3-carboxylate

The title compound was synthesized in 87% yield according to protocol Afrom 2-(4-iodophenyl)acetic acid and methyl2-amino-4-methylthiophene-3-carboxylate. ¹³C NMR (CDCl₃): δ 167.5,166.6, 149.8, 138.1, 134.8, 133.1, 131.4, 113.0, 112.3, 93.2, 51.5,43.3, 17.8; MH+ 416.0.

4.7.2. Methyl4-methyl-2-(2-(4-(pyridin-4-yl)phenyl)acetamido)thiophene-3-carboxylate

Methyl 2-(2-(4-iodophenyl)acetamido-4-methylthiophene-3-carboxylate(420.4 mg, 1.01 mmol), 4-pyridylboronic acid (Aldrich, 167 mg, 1.36mmol), tetrakis(triphenylphosphine)palladium(0) (123 mg, 0.11 mmol), andpotassium carbonate (565 mg, 4.1 mmol) were combined in DME (2 mL) andwater (1 mL) in a sealed tube, and heated to 80° C. over 17 h. Thereaction mixture was cooled to rt, then partitioned between EtOAc andwater. The organic layer was separated, washed (brine), dried (Na₂SO₄),filtered and concentrated under reduced pressure. Flash chromatography(EtOAc/hexanes) afforded the titled compound. ¹H NMR (CDCl₃): δ 11.3 (s,1H), 8.67 (dd, J=4.7, 1.4 Hz, 2H), 7.67 (d, J=8.2 Hz, 2H), 7.60-7.40 (m,4H), 6.38 (s, 1H), 3.88 (s, 2H), 3.80 (s, 3H), 2.33 (s, 3H); ¹³C NMR(CDCl₃): δ 167.7, 166.6, 150.3, 149.9, 147.8, 137.4, 134.8, 134.6,130.3, 127.7, 121.5, 113.0, 112.3, 51.5, 43.5, 17.8; MH+ 367.1.

4.7.3.N-(4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)thiophen-2-yl)-2-(4-(pyridin-4-yl)phenyl)acetamide

Acetamide oxime (66 mg, 0.89 mmol) was taken up in dry THF (1 mL) at rt,and sodium hydride (60% dispersion in mineral oil, 55 mg, 1.4 mmol) wasadded. After hydrogen evolution ceased, methyl4-methyl-2-(2-(4-pyridin-4-yl)phenyl)acetamido)thiophene-3-carboxylate(82 mg, 0.22 mmol) was added in one portion. The reaction was stirred atrt for 90 min, then at 50° C. for 21 h. The mixture was concentratedunder reduced pressure, then partitioned between ethyl acetate andwater. The organic layer was separated, and washed with saturated NaClsolution. The organic layer was dried (MgSO₄), filtered andconcentrated. HPLC purification of the crude residue afforded the titlecompound as a trifluoroacetic acid salt. ¹H NMR (CDCl₃): δ 11.6 (s, 1H),8.86 (dd, J=5.3, 1.4 H, 2H), 7.94 (dd, J=5.3, 1.4 H, 2H), 7.77 (d, J=8.2Hz, 2H), 7.61 (d, J=8.2 Hz, 2H), 6.54 (s, 1H), 3.99 (s, 2H), 2.51 (s,3H), 2.34 (s, 3H); MH+ 407.1.

4.8. Synthesis ofN-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(61)

4.8.1. Methyl 3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylate

Methyl 3 -(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylate wasprepared from methyl 3-aminothiophene-2-carboxylate (4.30 g, 27.3 mmol)and 2-(naphthalen-1yl)acetic acid (3.10 g, 27.3 mmol) according toprotocol A. Retention time (min)=8.738, method [7], MS(ESI) 326.1 (M+H).

4.8.2.N-(2-(3-Methyl-1,2,4-oxadiazol-5-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide

Sodium hydride (60% dispersion, 15 mg, 0.39 mmol) was added to asolution acetamide oxime (29 mg, 0.39 mmol) in THF (1 mL). The resultingmixture was stirred at room temperature for 10 minutes after which asolution of methyl3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylate (107 mg, 0.33mmol) in THF (1 mL) was added. The reaction mixture was stirred for 1 hand was subsequently diluted with ethyl acetate (10 mL), The resultingsolution was washed with brine (5 mL) and the organic phase was thendried (Na₂SO₄), filtered and concentrated under vacuum. The residue wasdissolved in THF (1 mL) and HCl (1 mL of a 10% aqueous solution wasadded. The mixture was stirred for 20 minutes after which ethyl acetate(10 mL) was added. The resulting solution was washed with brine (5 mL)and the organic phase was then dried (Na₂SO₄), filtered, concentratedunder vacuum and the residue was purified by preparative HPLC to giveN-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide.Retention time (min)=9.533, method [7], MS(ESI) 350.1 (M+H). ¹H NMR (300MHz, CDCl₃): δ 10.10 (s, 1H), 8.26 (d, J=5.4 Hz, 1H), 8.03 (d, J=9.3 Hz,2H), 7.50-7.49 (m, 5H), 4.27 (s, 2H), 2.14 (s, 3H).

Synthesis ofN-(3-(1,2,4-oxadiazol-3-yl)thiophen-2-yl)-2-(6,7-difluoro-2-oxoquinolin-1(2H)-yl)acetamide

4.9.1. N-(Thieno[2,3-d]pyrimidin-4-yl)hydroxylamine

4-chlorothieno[2,3-d]pyrimidine (340 mg, 1.99 mmol),hydroxylamine-hydrogen chloride (550 mg, 7.91 mmol), anddiisopropylethylamine (1 ml) in absolute ethanol (5 ml) was placed intoa preheated oil bath at 75° C. After stirring for 6 h, the solution wasconcentrated under reduced pressure.

4.9.2. (E)-Ethyl N-3-(1,2,4-oxadiazol-3-yl)thiophen-2-ylformimidate

N-(thieno[2,3-d]pyrimidin-4-yl)hydroxylamine and triethylorthoformate(10 ml) in ethanol (10 ml) was placed into a preheated oil bath at 100°C. for 4 h. The solution was concentrated to yield (E)-ethylN-3-(1,2,4-oxadiazol-3-yl)thiophen-2-ylformimidate. Method [8] retentiontime 4.08 min by HPLC (M+=224).

4.9.3. 3-(1,2,4-Oxadiazol-3-yl)thiophen-2-amine

(E)-Ethyl N-3-(1,2,4-oxadiazol-3-yl)thiophen-2-ylformimidate (82 mg, 365umol) and N-methylethane-1,2-diamine (0.30 ml, 3.40 mmol) in methanol (2ml) was placed into a preheated oil bath at 60° C. After stirring for 15min, the solution was concentrated under reduced pressure and theresidue was flash chromotraphed with 9:1, 4:1, 7:3, and 3:2 hexane:ethylacetate as the eluant to afford 18 mg (5.4% yield over three steps of3-(1,2,4-oxadiazol-3-yl)thiophen-2-amine. Method [6] retention time 4.08min by HPLC (M+ 168). ¹H NMR (300 MHz, CDCl₃): δ 8.70 (s, 1H), 7.22 (d,J=5.4 Hz, 1H), 6.45 (d, J=5.4 Hz, 1H).

4.9.4.N-(3-(1,2,4-oxadiazol-3-yl)thiophen-2-yl)-2-(6,7-difluoro-2-oxoquinolin-1(2H)-yl)acetamide

The title compound was prepared from3-(1,2,4-oxadiazol-3-yl)thiophen-2-amine (18 mg, 108 umol) and2-(6,7-difluoro-2-oxoquinolin-1(2H)-yl)acetic acid (32 mg, 134 umol)using protocol A. The crude product was purified by HPLC to yieldN-(3-(1,2,4-oxadiazol-3-yl)thiophen-2-yl)-2-(6,7-difluoro-2-oxoquinolin-1(2H)-yl)acetamide.Method [7] retention time 5.34 min by HPLC (M+=389) and (M+Na=411). ¹HNMR (300 MHz, CDCl₃): δ 11.06 (s, 1H), 8.69 (s, 1H), (d, J=9.9 Hz, 1H),7.42 (m, 2H), 7.35 (m, 1H), 6.98 (d, J=5.4 Hz, 1H), 6.86 (d, J=9.3 Hz,1H), 5.22 (s, 2H).

EXAMPLE 5 Synthesis of Thiazole Triazoles 5.1. Synthesis ofN-(4-(1H-1,2,4-triazol-5-yl)thiazol-5-yl)-2-(isoquinolin-5-yl)acetamide(62)

5.1.1. Methyl 5-(diphenylmethyleneamino)thiazole-4-carboxylate

A mixture of methyl 5-bromothiazole-4-carboxylate (3.51 g, 15.8 mmol),diphenylmethanimine (4.0 ml, 23.9 mmol), cesium carbonate (10.98 g, 33.7mmol), Pd₂(dba)₃.CHCl₃ (876 mg, 957 umol), and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 1.67 g, 2.89mmol) in toluene (30 ml) was heated at 80° C. for 18 h. Theheterogeneous mixture was directly flash chromatographed with 9:1, 4:1,7:3, 3:2 and 1:1 hexane:ethyl acetate as the eluant to yield 4.30 g (84%yield) of methyl 5-(diphenylmethyleneamino)thiazole-4-carboxylate as ayellow oil. Retention time (min)=6.41, method [7], MS(ESI) 323.0 (M+H).

5.1.2. Methyl 5-aminothiazole-4-carboxylate

Aqueous 3N HCl (1 mL) was added to a solution of methyl5-(diphenylmethyleneamino)thiazole-4-carboxylate (1.22 g, 3.81 mmol) inTHF (5 mL). The reaction mixture was stirred for 1 h and the white solidwhich had formed was isolated by filtration to give methyl5-aminothiazole-4-carboxylate (0.527 g, 2.72 mmol, 71%). Retention time(min)=0.422, method [7], MS(ESI) 159.0 (M+H).

5.1.3. Methyl 5-(2-(isoquinolin-5-yl)acetamido)thiazole-4-carboxylate

Methyl 5-(2-(isoquinolin-5-yl)acetamido)thiazole-4-carboxylate wasprepared from methyl 5-aminothiazole-4-carboxylate (0.132 g, 0.834 mmol)and 2-(isoquinolin-5-yl)acetic acid (0.163 g, 0.834 mmol) according toprotocol A. Retention time (min)=2.400, method [3], MS(ESI) 328.0 (M+H).

5.1.4. 5-(2-(Isoquinolin-5-yl)acetamido)thiazole-4-carboxamide

5-(2-(Isoquinolin-5-yl)acetamido)thiazole-4-carboxamide was preparedfrom methyl 5-(2-(isoquinolin-5-yl)acetamido)thiazole-4-carboxylate (210mg, 0.64 mmol) according to protocol H. Retention time (min)=2.507,method [3], MS(ESI) 313.0 (M+H).

5.1.5.N-(4-(1H-1,2,4-triazol-5-yl)thiazol-5-yl)-2-(isoquinolin-5-yl)acetamide

N-(4-(1H-1,2,4-triazol-5-yl)thiazol-5-yl)-2-(isoquinolin-5-yl)acetamidewas prepared from5-(2-(isoquinolin-5-yl)acetamido)thiazole-4-carboxamide (124 mg, 0.396mmol) according to protocol I. Retention time (min)=4.890, method [8],MS(ESI) 337.1 (M+H); ¹H NMR (300 MHz, CD₃OD): δ 9.75 (s, 1H), 8.45-8.59(m, 4H), 8.29-8.31 (m, 1H), 8.05-8.14 (m, 2H), 4.63 (s, 2H).

5.2. Synthesis of2-(isoquinolin-5-yl)-N-(4-(1-methyl-1H-1,2,4-triazol-5-yl)thiazol-5-yl)acetamide(63)

2-(Isoquinolin-5-yl)-N-(4-(1-methyl-1H-1,2,4-triazol-5-yl)thiazol-5-yl)acetamidewas prepared from 5-(2-Isoquinolin-5-yl)acetamido)thiazole-4-carboxamide(Example 5.1.4., 197 mg, 0.631 mmol) according to protocol J. Retentiontime (min)=1.196 method [7], MS(ESI) 351.1 (M+H); ¹H NMR (300 MHz,CD₃OD): δ 9.75 (s, 1H), 8.45-8.60 (m, 4H), 8.28 (d, J=7.6 Hz, 1H), 8.07(dd, J=8.8, 7.6 Hz, 1H), 7.73 (s, 1H), 4.61 (s, 2H), 4.27 (s, 3H).

EXAMPLE 6 Synthesis of 2-(2-pyridyl)-3-(1-naphthylacetylamino)thiophene(64)

6.1. 2-Iodo-3-(tert-butoxycarbonylamino)thiophene

A vial was charged with 199 mg (1.0 mmol)3-(tert-butoxycarbonylamino)thiophene, 164 mg (2.0 mmol) NaOAc, 4.0 mLHOAc, and a stir bar. The mixture was stirred at room temperature,giving a homogeneous solution “A”. A second vial was charged with 162 mg(1.0 mmol) iodine monochloride and 2.0 mL glacial acetic acid. Thesecond mixture was swirled at room temperature. This second homogeneoussolution “B” was added to solution “A” dropwise over three minutes. Awhite solid began to precipitate immediately. After the addition, themixture was allowed to stand overnight, at which time the white solidhad separated from the brown supernatant. With stirring, 200 uL sat.Na₂S₂O₃/H₂O was added, decolorizing the mixture from brown to yellow. 10mL water was added, and then the mixture was evaporated, affording asemi-solid light brown residue. The residue was partitioned betweenEtOAc and H₂O, and the separated EtOAc phase was washed (sat. NaHCO₃,then sat. NaCl). The EtOAc phase was filtered, and concentrated to give262 mg (81%) of the title compound as light brown crystals. ¹H NMR(CDCl₃, 300 MHz): δ 7.49 (bs, 1H), 7.45 (d, J=5.4 Hz, 1H), 6.50 (bs,1H), 1.54 (s, 9H). Method [5]: rt=1.40 min; m/z=269.9 (MH+ minusisobutylene).

6.2. 2-(2-Pyridyl)-3-(1-naphthylacetylamino)thiophene

A vial was charged with 255 mg (0.783 mmol)2-iodo-3-(tert-butoxycarbonylamino)-thiophene, 467 mg (1.27 mmol)2-(tributylstannyl)pyridine, 18 mg (0.015 mmol) Pd(PPh₃)₄, and 2 mLtoluene. The vial was flushed with nitrogen. The vial was shaken at 95°C. for 24 h. The cooled vial was opened, and TLC indicated consumptionof 2-iodo-3-(tert-butoxycarbonylamino)thiophene and formation of acomplex product mixture. The toluene was evaporated, and the residue wastreated with 3 mL CF₃CO₂H. After 5 h at rt, the CF₃CO₂H was evaporated,and the residue was partitioned between 1 M H₂SO₄ and toluene. Theaqueous phase was made basic by adding solid NaHCO₃, and then themixture was extracted with EtOAc. Evaporation of the EtOAc extractsprovided 75 mg of a 2:1 mixture of 2-(2-pyridinyl)-3-aminothiophene and2-(3-aminothiophene-2-yl)-3-aminothiophene, as determined by HPLCMS.

The title compound was prepared from the above mixture and1-naphthylacetic acid (230 mg, 1.23 mmol) according to protocol A. Theresidue was purified by flash chromatography using EtOAc/hexanes onsilica gel, affording 40 mg (15%) of the title compound as a whitesolid. ¹H NMR (CDCl₃, 300 MHz): δ 11.92 (bs, 1H), 8.26 (d, J=5.4, 1H),8.08 (dd, J=1.8 Hz, J=6.9 Hz, 1H), 7.93-7.88 (m, 2H), 7.59-7.46 (m, 6H),7.27 (d, J=8.1 Hz, 1H), .20 (d, J=6.3 Hz, 1H), 6.84 (dd, J=4.8 Hz, J=7.2Hz, 1H), 4.24 (s, 2H). ¹³C NMR (CDCl₃, 75 MHz) δ 153.5, 147.1, 138.3,136.7, 134.0, 132.6, 130.9, 128.9, 128.6, 128.4, 126.8, 126.1, 125.6,124.4, 124.1, 123.9, 120,1, 119.8, 116.9, 43.2. Method [5]: rt=1.67 min;MH+ 345.2.

EXAMPLE 7 Synthesis of Thiophene Pyrazoles 7.1. Synthesis ofN-(2-(1H-pyrazol-1-yl)thiophen-3-yl)-2-(4-methoxyphenyl)-acetamide (65)

7.1.1. 1-(3-Nitrothiophen-2-yl)-1H-pyrazole

Potassium tert-butoxide (2.28 g, 20.3 mmol) and 1H-pyrazole (2.02 g,29.7 mmol) in DMF (50 ml) was stirred for 30 min.2-chloro-3-nitrothiophene (2.56 g, 15.6 mmol) was added and the solutionwas placed into a preheated oil bath at 100° C. After stirring for 1 h,the solution was diluted with brine and extracted with diethyl ether.The combined organic extracts were dried over magnesium sulfate,filtered and concentrated under reduced pressure. The residue was flashchromatographed with 9:1, 4:1, 7:3, 3:2, and 1:1 hexane:ethyl acetate asthe eluant to yield impure 1-(3-nitrothiophen-2-yl)-1H-pyrazole. Method[1] Retention time 1.52 min by HPLC (MH+ 196).

7.1.2. 2-(1H-Pyrazol-1-yl)thiophen-3-amine

The title compound was prepared from1-(3-nitrothiophen-2-yl)-1H-pyrazole using protocol Q to yield impure2-(1H-pyrazol-1-yl)thiophen-3-amine. Method [3] Retention time 1.55 minby HPLC (MH+ 166).

7.1.3. N-(2-1H-Pyrazol-1-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide

The title compound was prepared from 2-(1H-pyrazol-1-yl)thiophen-3-amineand 2-(4-methoxyphenyl)acetic acid using protocol B. The solution wasdirectly purified by HPLC to yieldN-(2-(1H-pyrazol-1-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide.Method [7] Retention time 5.22 min by HPLC (MH+ 314). ¹H NMR (300 MHz,CDCl₃): δ 9.94 (broad s, 1H), 8.00 (d, J=5.7 Hz, 1H), 7.61 (d, J=2.7 Hz,1H), 7.39 (d, J=1.8 Hz, 1H), 7.27 (m, 2H), 6.94 (m, 3H), 6.35 (t, J=2.4Hz, 1H), 3.87 (s, 3H), 3.71 (s, 2H).

7.2. Synthesis of2-(4-methoxyphenyl)-N-(2-4-methyl-1H-pyrazol-1-yl)thiophen-3-yl)acetamide(66)

7.2.1. 4-Methyl-1-(3-nitrothiophen-2-yl)-1H-pyrazole

Potassium tert-butoxide (2.78 g, 24.8 mmol) and 4-methyl-1H-pyrazole(3.0 ml g, 37.3 mmol) in DMF (50 ml) was stirred for 30 min.2-chloro-3-nitrothiophene (3.08 g, 18.7 mmol) was added and the solutionwas placed into a preheated oil bath at 100° C. After stirring for 1 h,the solution was diluted with brine and extracted with diethyl ether.The combined organic extracts were dried over magnesium sulfate,filtered and concentrated under reduced pressure. The residue was flashchromatographed with 9:1, 4:1, 7:3, 3:2, and 1:1 hexane:ethyl acetate asthe eluant to yield 4-methyl-1-(3-nitrothiophen-2-yl)-1H-pyrazole.Method [1] Retention time 1.80 min by HPLC (MH+ 210).

7.2.2. 2-(4-Methyl-1H-pyrazol-1-yl)thiophen-3-amine

4-Methyl-1-(3-nitrothiophen-2-yl)-1H-pyrazole was treated with protocolQ to yield impure 2-(4-methyl-1H-pyrazol-1-yl)thiophen-3-amine. Method[3] Retention time 2.61 min by HPLC (MH+ 180).

7.2.3.2-(4-Methoxyphenyl)-N-(2-(4-methyl-1H-pyrazol-1-yl)thiophen-3-yl)acetamide

The title compound was prepared from2-(4-methyl-1H-pyrazol-1-yl)thiophen-3-amine and2-(4-methoxyphenyl)acetic acid using protocol B and purified by HPLC.Method [7] Retention time 6.16 min by HPLC (MH+ 328). ¹H NMR (300 MHz,CDCl₃): δ 9.93 (broad s, 1H), 7.97 (d, J=6.0 Hz, 1H), 7.38 (s, 1H), 7.19(s, 1H), 7.27 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.7Hz, 2H), 6.90 (d, J=6.0 Hz, 1H), 3.87 (s, 3H), 3.70 (s, 2H), 2.11 (s,3H).

7.3. Synthesis ofN-(2-(1H-pyrazole-3-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (67)

7.3.1.(E)-N-(2-(3-(Dimethylamino)acryloyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide

A solution of N-(2-acetylthiophen-3-yl-2-(naphthalen-1-yl)acetamide (165mg, 0.53 mmol) in N,N-dimethylformamide dimethyl acetal (0.2 mL, 1.50mmol) was heated at 80° C. for 2 h. The reaction mixture was partitionedbetween ethyl acetate and H₂O. The organic layer was washed with H₂O,dried (sodium sulfate), filtered and concentrated under reduced pressureto give the desiredN-(2-(3-(dimethylamino)acryloyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(185 mg, 95%) which was used without further purification. Method [4]m/z 387.0 (M+Na); rt=2.199 min.

7.3.2. N-(2-(1H-Pyrazol-3-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide

To a solution of(E)-N-(2-(3-(dimethylamino)acryloyl)thiophene-3-yl)-2-(naphthalen-1-yl)acetamide(185 mg, 0.51 mmol) in abs. ethanol (2 mL) was added hydrazine hydrate(0.2 ml, 4.11 mmol) and acetic acid (0.5 mL, 8.73 mmol). The reactionmixture was stirred at room temperature overnight under N₂ (g) inlet andthen concentrated under reduced pressure. The resulting residue waspartitioned between ethyl acetate and H₂O. The organic layer was dried(sodium sulfate), filtered and concentrated under reduced pressure. Theprecipitate that formed was washed with methanol and collectedfiltration to affordN-(2-(1H-pyrazol-3-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide (50mg, 30%). Method [7] m/z 334.0 (M+H); retention time=5.887. ¹H-NMR(DMSO-₆): δ 12.92 (broad s, 1H), 10.37 (s, 1H), 8.09 (d, J=7.7 Hz, 1H),7.92 (d, J=6.9 Hz, 2H), 7.86 (d, J=7.7 Hz, 1H), 7.77 (s, 1H), 7.66 (d,J=5.3 Hz, 1H), 7.61-7.47 (m, 4H), 7.36 (d, J=5.3 Hz, 1H), 6.36 (d, J=2.4Hz, 1H), 4.19 (s, 2H).

7.4. Synthesis ofN-(2-(1-methyl-1H-pyrazol-3-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(68)

To a solution of(E)-N-(2-(3-(dimethylamino)acryloyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(Example 7.3.1., 143 mg, 0.39 mmol) in abs. ethanol (2 mL) was addedmethyl hydrazine (0.2 mL, 3.80 mmol) and acetic acid (0.5 mL, 8.73mmol). The reaction mixture was stirred at room temperature overnightunder N₂ (g) inlet and then concentrated under reduced pressure. Theresulting residue was partitioned between ethyl acetate and H₂O. Theorganic layer was dried (sodium sulfate), filtered and concentratedunder reduced pressure. Purification by flash column chromatography(silica, 20:80 ethyl acetate/hexane) yieldedN-(2-(1-methyl-1H-pyrazol-3-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(27 mgs, 20%). Method [7]0 m/z 348.0 (M+H); retention time=5.328. ¹H-NMR(CDCl₃): δ 7.96 (d, J=5.2 Hz, 2H), 7.94-7.91 (m, 1H), 7.86 (d, J=7.8 Hz,1H), 7.56-7.53 (m, 2H), 7.41 (d, J=7.8 Hz, 1H), 7.36 (d, J=9.1 Hz, 1H),7.32 (d, J=5.2 Hz, 1H), 7.15 (s, 1H), 7.09 (d, J=1.9 Hz, 1H), 5.17 (d,J=1.9 Hz, 1H), 4.13 (s, 2H), 3.45 (s, 3H).

7.5. Synthesis ofN-(2-(5-methyl-1H-pyrazol-3-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(69)

7.5.1.(E)-N-(2-(3-(Dimethylamino)but-2-enoyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide

A solution of N-(2-acetylthiophen-2-yl)-2-(naphthalen-1-yl)acetamide(197 mg, 0.64 mmol) in N,N-dimethylacetamide dimethyl acetal (0.3 mL,2.05 mmol) was heated at 80° C. for 2 h. The reaction mixture waspartitioned between ethyl acetate and H₂O. The organic layer was washedwith H₂O, dried (sodium sulfate), filtered and concentrated to give thedesiredN-(2-(3-(dimethylamino)but-2-enoyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(139 mg, 58%) which was used without further purification.

7.5.2.N-(2-(5-methyl-1H-pyrazol-3-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide

To a solution of(E)-N-(2-(3-(dimethylamino)but-2-enoyl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(139 mg, 0.37 mmol) in abs. ethanol (2 mL) was added hydrazine hydrate(1 mL, 62.91 mmol) and acetic acid (0.5mL, 8.73 mmol). The reactionmixture was stirred at room temperature overnight under N₂ (g) inlet andthen concentrated under reduced pressure. The resulting residue waspartitioned between ethyl acetate and H₂O. The organic layer was dried(sodium sulfate), filtered and concentrated under reduced pressure.Purification by flash column chromatography (silica, 20:80 ethylacetate/hexane) yieldedN-(2-(5-methyl-1H-pyrazol-3-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(20 mgs, 16%). Method [7] m/z 348.1 (M+Na); retention time=6.791. ¹H-NMR(CDCl₃): δ 10.28 (broad s, 1H), 8.07 (d, J=5.8 Hz, 2H), 7.91 (d, J=4.5Hz, 2H), 7.53 (d, J=5.8 Hz, 2H), 7.53 (s, 1H), 7.50 (d, J=4.5 Hz, 2H),7.08 (d, J=5.2 Hz, 1H), 5.88 (s, 1H), 4.23 (s, 2H), 2.19 (s, 3H).

EXAMPLE 8 Thiophene Tetrazole Analogs 8.1. Synthesis ofN-(3-(2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)-acetamide (70)

8.1.1.2-(4-Methoxyphenyl)-N-(2-(4-methyl-1H-pyrazol-1-yl)thiophen-3-yl)acetamide

The title compound was synthesized from 2-(4-methoxyphenyl)acetic acidand 2-aminothiophene-3-carbonitrile using protocol B. The crude productwas purified using normal phase chromatography with 9:1, 4:1, 7:3, and3:2 hexane:ethyl acetate as the eluant to yieldN-(3-cyanothiophen-2-yl)-2-(4-methoxyphenyl)acetamide. Method [1]Retention time 1.81 min by HPLC (MH+ 307).

8.1.2.N-(3-(2H-Tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)-acetamide

N-(3-cyanothiophen-2-yl)-2-(4-methoxyphenyl)acetamide (285 gm, 1.05mmol), and azidotributylstannane (614 mg, 1.85 mmol) in toluene (10 ml)was placed into a preheated oil bath at 100° C. After stirring for 6 h,The solution was concentrated and directly purified by HPLC to yieldN-(3-(2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide.Method [7] Retention time 4.92 min by HPLC (MH+ 316). ¹H NMR (300 MHz,DMSO): δ 11.05 (s, 1H), 7.37 (d, J=6.0 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H),7.23 (d, J=6.0 Hz, 1H), 6.94 (d, J=8.4 Hz, 2H), 3.88 (s, 2H), 3.76 (s,3H).

8.2. Synthesis of2-(4-methoxyphenyl)-N-(3-(2-methyl-2H-tetrazol-5-yl)thiophen-2-yl)acetamide(71)

Iodomethane (0.20 ml, 3.21 mmol) was added to a heterogeneous mixture ofN-(3-(2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide(Example 8.1., 620 mg, 1.97 mmol) and potassium carbonate (1.36 g, 9.84mmol) in DMF (10 ml). After stirring for 72 h, the solution was dilutedwith water and extracted with methylene chloride. The combined organicextracts were dried over magnesium sulfate, filtered and concentratedunder reduced pressure. The residue was directly purified by HPLC toyield2-(4-methoxyphenyl)-N-(3-(2-methyl-2H-tetrazol-5-yl)thiophen-2-yl)acetamide.Method [7] Retention time 6.03 min by HPLC (MH+ 330). ¹H NMR (300 MHz,CDCl₃): δ 10.59 (s, 1H), 7.34 (d, J=6.0 Hz, 1H), 7.33 (d, J=8.7 Hz, 2H),7.00 (d, J=8.7 hz, 2H), 6.91 (d, J=6.0 Hz, 1H), 4.28 (s, 3H), 3.89 (s,3H), 3.86 (s, 2H).

8.3. Synthesis ofN-(3-(2-(methoxymethyl)-2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide(72)

Chloromethyl methyl ether (0.20 ml, 2.63 mmol) was added to aheterogeneous mixture ofN-(3-(2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide(Example 8.1., 580 mg, 1.84 mmol) and potassium carbonate (1.36 g, 9.84mmol) in DMF (10 ml). After stirring for 72 h, the solution was dilutedwith water and extracted with methylene chloride. The combined organicextracts were dried over magnesium sulfate, filtered and concentratedunder reduced pressure. The residue was directly purified by HPLC toyieldN-(3-(2-methoxymethyl)-2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide.Method [7] Retention time 6.60 min by HPLC (MH+ 360). ¹H NMR (300 MHz,CDCl₃): δ 10.58 (s, 1H), 7.47 (d, J=5.7 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H),7.00 (d, J=8.4 Hz, 2H), 6.93 (d, J=5.7 Hz, 1H), 5.77 (s, 2H), 3.87 (s,3H), 3.86 (s, 2H), 3.37 (s, 3H).

8.4. Synthesis ofN-(3-(1-(methoxymethyl)-1H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide(72a)

The title compound was isolated during the purification ofN-(3-(2-(methoxymethyl)-2H-tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)acetamide,above. Method [7]Retention time 6.60 min by HPLC (MH+ 660).

EXAMPLE 9 Synthesis of Thiophene Imidazoles 9.1. Synthesis ofN-(2-(1-methyl-1H-imidazol-2-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide(73)

9.1.1. 2-(Naphthalen-1-yl)-N-(thiophen-3-yl)acetamide

2-(naphthalen-1-yl)acetamide (14.00 g, 75.6 mmol), 3-iodothiophene(10.15 g, 48.3 mmol), trans-1,2diaminocyclohexane (3.0 ml, 25.0 mmol),cuprous iodide (1.97 g, 10.3 mmol), and potassium carbonate (13.66 g,98.8 mmol) in dioxane (50 ml) was placed into a preheated oil bath at95° C. After stirring for 18 h, the heterogeneous mixture was dilutedwith water and extracted with methylene chloride. The combined organicextracts were dried over magnesium sulfate, filtered and concentratedunder reduced pressure. The residue was flash chromatographed with 19:1,9:1, 17:3, and 4:1 methylene chloride:ethyl acetate as the eluant toyield 12.26 g (95% yield) of2-(naphthalen-1-yl)-N-(thiophen-3-yl)acetamide as a brown solid. Method[7] Retention time 2.07 min by HPLC (MH+ 268).

9.1.2. N-(2-Iodothiophen-3-yl)-2-(naphthalen-1-yl)acetamide

2-(naphthalen-1-yl)-N-(thiophen-3-yl)acetamide (7.50 g, 28.1 mmol) andN-iodosuccinimide (7.12 g, 31.6 mmol) in acetonitrile (100 ml) wasplaced into a preheated oil bath at 75° C. After stirring for 18 h, thesolution was concentrated under reduced pressure. The residue was flashchromatographed with 99:1, 49:1, 24:1, and 23:2 methylene chloride:ethylacetate as the eluant to yield impureN-(2-iodothiophen-3-yl)-2-(naphthalen-1-yl)acetamide. Method [1]Retention time 2.32 min by HPLC (MH+ 394).

9.1.3.N-(2-(1-Methyl-1H-imidazol-2-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide

This molecule was synthesized fromN-(2-iodothiophen-3-yl)-2-(naphthalen-1-yl)acetamide and1-methyl-2-(tributylstannyl)-1H-imidazole according to protocol E. Theresidue was directly purified by HPLC to yieldN-(2-(1-methyl-1H-imidazol-2-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide.Method [7] Retention time 3.41 min by HPLC (MH+ 348). ¹H NMR (300 MHz,CDCl₃): δ 10.27 (s, 1H), 7.87 (m, 3H), 7.51 (m, 6H), 6.91 (d, J=1.5 hz,1H), 6.82 (d, J=1.5 Hz, 1H), 4.15 (s, 3H), 3.68 (s, 2H).

9.2. Synthesis of2-(4-methoxyphenyl)-N-(2-(1-methyl-1H-imidazol-4-yl)thiophen-3-yl)acetamide(74)

9.2.1. 1-methyl-4-(tributylstannyl)-1H-imidazole

3M-Ethyl magnesium bromide in THF (11.0 ml, 33.0 mmol) was addeddropwise to a solution of 4-iodo-1-methyl-1H-imidazole (5.61 g, 27.0mmol) in THF (50 ml) at −78° C. After stirring for 2 h, tributyltinchloride (8.0 ml, 29.5 mmol) was added. After stirring for an additional24 h, the solution was concentrated under reduced pressure. The residuewas flash chromatographed (hexane:ethyl acetate) to yield1-methyl-4-(tributylstannyl)-1H-imidazole. Method [7] Retention time7.34 min by HPLC (MH+ 373).

9.2.2. 1-Methyl-4-(3-nitrothiophen-2-yl)-1H-imidazole

The title compound was prepared from 2-chloro-3-nitrothiophene (2.57 g,15.7 mmol) and 1-methyl-4-(tributylstannyl)-1H-imidazole (8.64 g, 23.3mmol) using protocol E except the reaction was heated to 90° C. (ratherthan 95° C.) and was purified by flash chromatography (hexane:ethylacetate). Method [1] Retention time 0.57 min by HPLC (MH+ 210).

9.2.3. 2-(1-Methyl-1H-imidazol-4-yl)thiophen-3-amine

1-methyl-4-(3-nitrothiophen-2-yl)-1H-imidazole was reduced according toprotocol F to yield 2-(1-methyl-1H-imidazol-4-yl)thiophen-3-amine.Method [6] Retention time 0.35 min by HPLC (MH+ 180).

9.2.4.2-(4-Methoxyphenyl)-N-(2-(1-methyl-1H-imidazol-4-yl)thiophen-3-yl)acetamide

The title compound was prepared from2-(1-methyl-1H-imidazol-4-yl)thiophen-3-amine and2-(4-methoxyphenyl)acetic acid using protocol B and was purified byHPLC. Method [8] Retention time 3.55 min by HPLC (MH+ 328). ¹H NMR (300MHz, DMSO): δ 10.37 (s, 1H), 8.33 (s, 1H), 7.48 (3m, H), 7.26 (d, J=8.4Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), (s, 6H), 3.60 (s, 2H).

9.3 Synthesis ofN-(2-(1H-imidazol-4-yl)thiophen-3-yl)-2-(4-methoxyphenyl)-acetamide (75)

9.3.1. 4-(Tributylstannyl)-1-trityl-1H-imidazole

3 M Ethyl magnesium bromide in THF (5.0 ml, 15.0 mmol) was addeddropwise to a solution of 4-iodo-1-trityl-1H-imidazole (4.44 g, 10.2mmol) in THF (100 ml) at −78° C. After stirring for 2 h, tributyltinchloride (5.0 ml, 18.4 mmol) was added. After stirring for an additional2 h, the solution was concentrated under reduced pressure. The residuewas flash chromatographed with 19:1; 9:1, 17:3, and 4:1 hexane:ethylacetate as the eluant to yield 7.72 g of impure4-(tributylstannyl)-1-trityl-1H-imidazole as a yellow solid. Method [7]Retention time 10.89 min by HPLC (MH+ 601).

9.3.2. 4-(3-Nitrothiophen-2-yl)-1-trityl-1H-imidazole

The title compound was prepared from 2-chloro-3-nitrothiophene and4-(tributylstannyl)-1-trityl-1H-imidazole according to Protocol E.Yield: 2.43 g (56% over 2 steps from 4-iodo-1-trityl-1H-imidazole) of4-(3-nitrothiophen-2-yl)-1-trityl-1H-imidazole as a greenish-yellowsolid. Method [7] Retention time 9.92 min by HPLC (M+Na=460).

9.3.3. 2-(1-Trityl-1H-imidazol-4-yl)thiophen-3-amine

The title compound was prepared from4-(3-nitrothiophen-2-yl)-1-trityl-1H-imidazole using protocol F (1.27 g,95% yield) as a red viscous liquid. Method [7] Retention time 5.51 minby HPLC (M+Na=430).

9.3.4.2-(4-Methoxyphenyl)-N-(2-(1-trityl-1H-imidazol-4-yl)thiophen-3-yl)acetamide

The title compound was prepared from2-(1-trityl-1H-imidazol-4-yl)thiophen-3-amine and2-(4-methoxyphenyl)acetic acid using protocol B (561 mg, 59%) as a brownsolid. Method [7] Retention time 9.46 min by HPLC (MH+ 556).

9.3.5.N-(2-(1H-Imidazol-4-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide

2-(4-Methoxyphenyl)-N-(2-(1-trityl-1H-imidazol-4-yl)thiophen-3-yl)acetamide(561 mg, 1.01 mmol) in TFA (10 ml) was stirred for 1 h. The solution wasconcentrated under reduced pressure and the residue was directlypurified by HPLC to yieldN-(2-(1H-imidazol-4-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide.Method [8] Retention time 3.37 min by HPLC (MH+ 314). ¹H NMR (300 MHz,DMSO): δ 10.28 (s, 1H), 8.60 (s, 1H), 7.59 (s, 1H), 7.53 (d, J=5.7 Hz,1H), 7.49 (d, J=5.7 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz,2H), 3.73 (s, 3H).

9.4. Synthesis ofN-(2-(1H-imidazol-4-yl)thiophen-3-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-acetamide(76)

9.4.1.2-(2-Oxo-3,4-dihydroquinolin-1(2H)-yl)-N-(2-(1-trityl-1H-imidazol-4-yl)thiophen-3-yl)acetamide

The title compound was prepared from2-(1-trityl-1H-imidazol-4-yl)thiophen-3-amine and2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid using protocol B (269mg, 32%). Method [7] Retention time 9.32 min by HPLC (MH+ 595).

9.4.2.N-(2-(1H-Imidazol-4-yl)thiophen-3-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-oxo-3,4-dihdyroquinolin-1(2H)-yl)-N-(2-(1-trityl-1H-imidazol-4-yl)thiophen-3-yl)acetamide(269 mg, 452 umol) as described in Example 9.3.5. and was purified byHPLC. Method [8] Retention time 3.74 min by HPLC (MH+ 353). ¹H NMR (300MHz, DMSO): δ 10.58 (s, 1H), 8.52 (s, 1H), 7.65 (s, 1H), 7.54 (s, 2H),7.22 (m, 2H), 6.99 (m, 2H), 4.68 (s, 2H), 2.95 (m, 2H), 2.66 (m, 2H).

9.5. Synthesis of2-(4-methoxyphenyl)-N-(2-(2-methyl-1H-imidazol-4-yl)thiophen-3-yl)acetamide(77)

9.5.1. 2-Methyl-4-(tributylstannyl)-1-trityl-1H-imidazole

3 M Ethyl magnesium bromide in THF (6.0 ml, 18.0 mmol) was addeddropwise to a solution of 4-iodo-2-methyl-1-trityl-1H-imidazole (5.30 g,11.8 mmol) in THF (100 ml) at −78° C. After stirring for 2 h,tributyltin chloride (5.0 ml, 18.4 mmol) was added. After stirring foran additional 2 h, the solution was diluted with water and extractedwith methylene chloride. The combined organic extracts were dried overmagnesium sulfate, filtered and concentrated under reduced pressure toyield 8.49 g of impure2-methyl-4-(tributylstannyl)-1-trityl-1H-imidazole as a orange liquid.Method [7] Retention time 11.32 min by HPLC (MH+ 615).

9.5.2. 2-Methyl-4-(3-nitrothiophen-2-yl)-1-trityl-1H-imidazole

The title compound was prepared from2-methyl-4-(tributylstannyl)-1-trityl-1H-imidazole and2-chloro-3-nitrothiophene using protocol E (3.43 g, 76% over 2 steps) .Method [7] Retention time 8.87 min by HPLC (M+Na=474).

9.5.3. 2-(2-Methyl-1-trityl-1H-imidazol-4-yl)thiophen-3-amine

The title compound was prepared from2-methyl-4-(3-nitrothiophen-2-yl)-1-trityl-1H-imidazole using protocol F(1.33 g, 100% yield). Method [7] Retention time 5.42 min by HPLC(M+Na=444).

9.5.4.2-(4-Methoxyphenyl)-N-(2-(2-methyl-1-trityl-1H-imidazol-4-yl)thiophen-3-yl)acetamide

The title compound was prepared from2-(2-methyl-1-trityl-1H-imidazol-4-yl)thiophen-3-amine and2-(4-methoxyphenyl)acetic acid using protocol B (540 mg, 57%). Method[7] Retention time 7.42 min by HPLC (MH+ 570).

9.5.5.2-(4-Methoxyphenyl)-N-(2-(2-Methyl-1H-imidazol-4-yl)thiophen-3-yl)acetamide

2-(4-methoxyphenyl)-N-(2-(2-methyl-1-trityl-1H-imidazol-4-yl)thiophen-3-yl)acetamide(540 mg, 918 mmol) in TFA (10 ml) was stirred for 1 h. The solution wasconcentrated under reduced pressure and the residue was directlypurified by HPLC to yield2-(4-methoxyphenyl)-N-(2-(2-methyl-1H-imidazol-4-yl)thiophen-3-yl)acetamide.Method [8] Retention time 3.52 min by HPLC (MH+ 328). ¹H NMR (300 MHz,DMSO): δ 10.02 (s, 1H), 7.60 (d, J=5.4 Hz, 1H), 7.53 (s, 1H), 7.40 (d,J=5.4 Hz, 1H), 7.23 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.9 Hz, 2H), 3.73 (s,3H).

9.6 Synthesis ofN-(2-(2-methyl-1H-imidazol-4-yl)thiophen-3-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide(78)

9.6.1.N-(2-(2-Methyl-1-trityl-1H-imidazol-4-yl)thiophen-3-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide

The title compound was prepared from2-(2-methyl-1-trityl-1H-imidazol-4-yl)thiophen-3-amine and2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid using protocol B (125mg). Method [7] Retention time 7.33 min by HPLC (MH+ 609).

9.6.2.N-(2-(2-Methyl-1H-imidazol-4-yl)thiophen-3-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide

N-(2-(2-methyl-1-trityl-1H-imidazol-4-yl)thiophen-3-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide(125 mg, 205 mmol) in TFA (5 ml) was stirred for 1 h. The solution wasconcentrated under reduced pressure and the residue was directlypurified by HPLC to yield-(2-(2-methyl-1H-imidazol-4-yl)thiophen-3-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide.Method [8] Retention time 4.05 min by HPLC (MH+ 367). ¹H NMR (300 MHz,DMSO): δ 10.28 (s, 1H), 7.57 (m, 2H), 7.43 (d, J=4.8 Hz, 2H), 7.22 (m,2H), 6.99 (m, 2H), 4.68 (s, 2H), 2.92 (m, 2H), 2.59 (m, 2H), 2.46 (s,3H).

9.7. Synthesis ofN-(2-(1H-imidazol-1-yl)thiophen-3-yl)2-(naphthalen-1-yl)acetamide (79)

9.7.1. 1-(3-Nitrothiophen-2-yl)-1H-imidazole

Imidazole (860 mg, 12.63 mmol) was added to a solution of2-chloro-3-nitro-thiophene (1 g, 6.10 mmol) in abs. ethanol (20 mL). Thereaction mixture was heated to reflux in a sealed tube for 3 days andthen concentrated under reduced pressure. Purification by flashchromatography (silica, 25:75 ethyl/hexane) gave1-(3-nitrothiophen-2-yl)-1H-imidazole (540 mg, 45%). See Erker, T. J. etal., J. Heterocyclic. Chem. 39 (2002) 857-861. Method [3 ]m/z 195.9(M+H); retention time=0.615.

9.7.2. 2-(1H-Imidazol-1-yl)thiophen-3-amine

The title compound was prepared from1-(3-nitrothiophen-2-yl)-1H-imidazole (540 mg, 2376 mmol) using theprocedures of Example 1.97.2 (431 mg, 94%) and was used without furtherpurification. Method [4] m/z 166.0 (M+H); retention time=0.227.

9.7.4.N-(2-(1H-Imidazol-1-yl)thiophen-2-yl)-2-(naphthalen-1-yl)acetamide

To a mixture of 1-naphthyl acetic acid and2-(1H-imidazol-1-yl)thiophen-3-amine in anhydrous CH₂Cl₂ was addedO-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyl uroniumhexafluorophosphate and 4-methymorpholine. A small amount of DMF wasadded to help starting material reagents go into solution. The reactionmixture was stirred overnight under N₂ (g) inlet and evaporated underreduced pressure. The resulting residue was purified by flash columnchromatography (silica, 10:90 methanol/methylene chloride) to affordN-(2-(1H-imidazol-1-yl)thiophen-3-yl)2-naphthalen-1-yl)acetamide (209mg, 33%). The desired product was purified by preparative HPLC. Method[8] m/z 334.1 (M+H); retention time=4.885. ¹H-NMR (CD₃OD): δ 8.83 (s,1H), 7.89-7.80 (m, 2H), 7.77 (d, J=7.8 Hz, 1H), 7.51 (d, J=6.3 Hz, 2H),7.48-7.32 (m, 5H), 7.17 (d, J=6.3 Hz, 2H), 4.08 (s, 2H).

9.8. Synthesis of2-(4-methoxyphenyl)-N-(2-(4-methyl-1H-imidazol-1-yl)thiophen-3-yl)acetamide(80)

9.8.1. 4-Methyl-1-(3-nitrothiophen-2-yl)-1H-imidazole

4-methyl-1-(3-nitrothiophen-2-yl)-1H-imidazole was prepared from2-chloro-3-nitrothiophene and 4-methyl-1H-imidazole according to theprocedure described in Example 9.7.1., above. Purification by flashcolumn chromatography (silica, 40:60 ethyl acetate/hexane) gave thenitro intermediate (1.26 g, 49%). ¹H-NMR (CDCl₃): δ 7.67 (s, 1H), 7.59(d, J=6.1 Hz, 1H), 7.19 (d, J=6.1 Hz, 1H), 6.89 (s, 1H), 2.27 (s, 3H).

9.8.2. 2-(4-Methyl-1H-imidazol-1-yl)thiophen-3-amine

2-(4-methyl-1H-imidazol-1-yl)thiophen-3-amine was prepared from4-methyl-1-(3-nitrothiophen-2-yl)-1H-imidazole according to theprocedure described in Example 9.7.2., above. The amine intermediated(1.52 g, quantitative) was used without further purification. Method [4]m/z 180.1 (M+H); retention time=0.236.

9.8.3.2-(4-Methoxyphenyl)-N-(2-(4-methyl-1H-imidazol-1-yl)thiophen-3-yl)acetamide

2-(4-methoxyphenyl)-N-(2-(4-methyl-1H-imidazol-1-yl)thiophen-3-yl)acetamidewas prepared from 2-(4-methoxyphenyl)acetic acid and2-(4-methyl-1H-imidazol-1-yl)thiophen-3-amine according to the proceduredescribed in Example 9.7.3., above. Purification by flash columnchromatography afforded the final product (silica, 75:25 ethylacetate/hexane) (77 mg, 6%). Method [7] m/z 328.0 (M+H); retentiontime=1.001. ¹H-NMR (CDCl): δ 8.00 (broad s, 1H), 7.77 (d, J=6.4 Hz, 1H),7.16 (s, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 6.50 (s,1H), 3.81 (s, 3H), 3.65 (s, 2H), 2.15 (d, J=0.9 Hz, 2H).

EXAMPLE 10 Thiophene Pyrazine Analogs 10.1. Synthesis of2-(4-methoxyphenyl)-N-(2-(pyrazin-2-yl)thiophen-3-yl)acetamide (81)

10.1.1. 2-(3-Nitrothiophen-2-yl)pyrazine

The title compound was prepared from 2-(tributylstannyl)pyrazine and2-chloro-3-nitrothiophene using protocol E and was purified by flashchromatography (hexane:ethyl acetate). Method [7] Retention time 2.38min by HPLC (MH+ 208).

10.1.2. 2-(Pyrazin-2-yl)thiophen-3-amine

The title compound was prepared from 2-(3-nitrothiophen-2-yl)pyrazineusing protocol F. Method [8] Retention time 2.17 min by HPLC (MH+ 178).

10.1.3. 2-(4-methoxyphenyl)-N-(2-(pyrazin-2-yl)thiophen-3-yl)acetamide

The title compound was prepared from 2-(pyrazin-2-yl)thiophen-3-amineand 2-(4-methoxyphenyl)acetic acid according to protocol B and waspurified by HPLC. Method [7] Retention time 5.91 min by HPLC (MH+ 326).¹H NMR (300 MHz, DMSO): δ s (11.02, 1H), 8.81 (d, J=0.9 Hz, 1H), 8.45(d, J=2.7 Hz, 1H), 8.26 (m, 1H), 7.92 (d, J=5.4 Hz, 1H), 7.74 (d, J=5.4Hz, 1H), 7.33 (d, 8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 3.78 (s, 3H),3.72 (s, 2H).

10.2 Synthesis ofN-(4-cyano-3-(pyrazin-2-yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamide

10.2.1. 4-Bromo-5-nitrothiophene-3-carbonitrile

The title compound (2.8 g, 71%) was prepared from4-bromothiophene-3-carbonitrile (2.9 g, 15.5 mmol) according to theprocedure described in U.S. Patent Application Publication 20080214528(p. 25). R_(f)=0.48 (20% EtOAc/hexanes; silica); ¹H NMR (300 MHz,CDCl₃): δ 8.12 (s, 1H).

10.2.2. 5-Nitro-4-(pyrazin-2-yl)thiophene-3-carbonitrile

To a solution of 4-bromo-5-nitrothiophene-3-carbonitrile (312 mg, 1.34mmol) in dioxane (4 mL) was addedtetrakis(triphenylphosphine)palladium(0) (154 mg, 0.133 mmol) andtributylstannylpyrazine (794 mg, 2.15 mmol). This was heated bymicrowave irradiation to 140° C. for 30 min. The reaction mixture wasconcentrated under reduced pressure, and the residue purified by flashchromatography to afford the titled compound (166 mg, 53%): R_(f)=0.33(20% EtOAc/hexanes; silica); HPLC method [4], retention time=1.45 min;MS(ESI) 233.0 (MH+).

10.2.3. 5-Amino-4-(pyrazin-2-yl)thiophene-3-carbonitrile

To 5-nitro-4-(pyrazin-2-yl)thiophene-3-carbonitrile (166 mg, 0.72 mmol)in conc HCl (2 mL) at rt was added tin(II) chloride (327 mg, 1.7 mmol).This was stirred at rt for 2 h, whereupon the reaction mixture wasbasified with aqueous NaOH and extracted with EtOAc. The combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated to givea brown oil (31 mg, 21%). HPLC method [4], retention time=1.458 min;MS(ESI) 203.1 (MH+).

10.2.4.N-(4-cyano-3-(pyrazin-2-yl)thiophen-2-yl)-2-(quinolin-5-yl)acetamide

The title compound was synthesized from5-amino-4-(pyrazin-2-yl)thiophene-3-carbonitrile (30.5 mg, 0.15 mmol)and 2-(quinolin-5-yl)acetic acid hydrochloride (36 mg, 0.16 mmol)according to protocol A. The product was purified by HPLC method [4],retention time=1.393 min; MS(ESI) 372.1 (MH+); ¹H NMR (300 MHz, CD₃OD):δ 9.30 (d, J=1.5 Hz, 1H), 9.06 (dd, J=4.8, 1.3 Hz, 1H), 8.99 (d, J=8.5Hz, 1H), 8.51 (d, J=2.6 Hz, 1H), 8.29 (t, J=1.9 Hz, 1H), 8.20 (d, J=8.6Hz, 1H), 8.09 (dd, J=8.6, 7.1 Hz, 1H), 7.95 (s, 1H), 7.93 (d, J=6.7 Hz,1H), 7.86 (dd, J=8.6, 4.9 Hz, 1H), 4.55 (s, 2H).

EXAMPLE 11 Synthesis of2-(isoquinolin-5-yl)-N-(4-(pyrazin-2-yl)thiazol-5-yl)acetamide (82)

11.1. tert-butyl 4-bromothiazol-5-ylcarbamate

To a solution of tert-butyl thiazol-5-ylcarbamate (WO 2007/071955) (607mg, 3.0 mmol) in chloroform (50 mL) was added N-bromosuccinimide (542mg, 3.04 mmol) at 0° C. After 1 h, reaction was quenched by addition ofsaturated NaHCO₃ solution (50 mL). The layers were separated, and themixture extracted with CHCl₃ (3×50 mL). The combined organic extractswere dried (MgSO₄), filtered and concentrated. ¹H NMR (CDCl₃): δ 8.37(d, J=0.6 Hz, 1H), 7.05 (br s, 1H), 1.55 (s, 9H); MH+ 278.9.

11.2. tert-Butyl 4-(pyrazin-2-yl)thiazol-5-ylcarbamate

A mixture of tert-butyl 4-bromothiazol-5-ylcarbamate (420 mg, 1.5 mmol),tetrakis(triphenylphosphine)palladium(0) (170 mg, 0.15 mmol) and2-tributylstannylpyrazine (930 mg, 2.5 mmol) in anhydrous dioxane (4 mL)was heated to 140° C. in a microwave reactor for 2 h. The reactionmixture was then concentrated in vacuo and purified by flashchromatography (EtOAc/hexanes) to give the desired product (260 mg,62%). ¹H NMR (CDCl₃): δ 11.10 (s, 1H), 9.47 (d, J=1.4 Hz, 1H), 8.52 (t,J=2.0 Hz, 1H), 8.45 (d, J=2.7 Hz, 1H), 8.40 (s, 1H), 1.58 (s, 9H); MH+279.0.

11.3. 2-(Isoquinolin-5-yl)-N-(4-(pyrazin-2-yl)thiazol-5-yl)acetamide

To a solution of tert-butyl 4-(pyrazin-2-yl)thiazol-5-ylcarbamate (260mg, 0.94 mmol) in CH₂Cl₂ (1 mL) at 0° C. was added trifluoroacetic acid(1 mL) and the mixture was allowed to warm to rt over 1 h. The solventwas removed in vacuo and the crude product was used without furtherpurification.

The crude 4-(pyrazin-2-yl)thiazol-5-amine was coupled with2-isoquinolin-5-yl)acetic acid hydrochloride using procedure A and waspurified by HPLC purified to afford desired material as a whitetrifluoroacetic acid salt (107 mg). Method [8]: rt=3.71 min; ¹H NMR(CDCl₃): δ 12.16 (s, 1H), 9.80 (s, 1H), 9.48 (d, J=1.2 Hz, 1H), 8.64 (d,J=6.4 Hz, 1H), 8.47 (s, 1H), 8.45 (d, J=2.7 Hz, 1H), 8.39 (d, J=8.5 Hz,1H), 8.31 (d, J=6.5 Hz, 1H), 8.15 (d, J=7.2 Hz, 1H), 8.10-7.98 (m, 2H),4.45 (s, 2H); MH+ 348.0

EXAMPLE 12 Synthesis ofN-(4,4′-bithiazol-5-yl)-2-(isoquinolin-5-yl)acetamide (83)

12.1. tert-Butyl 4,4′-bithiazol-5-ylcarbamate

A mixture of tert-butyl 4-bromothiazol-5-ylcarbamate (590 mg, 2.1 mmol),tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.21 mmol) and4-tributylstannylthiazole (1.18 g, 3.2 mmol) in anhydrous dioxane (5 mL)was heated to 140° C. in a microwave reactor for 1 h. The reactionmixture was then concentrated in vacuo and purified by flashchromatography (EtOAc/hexanes elution) to give the desired product (420mg, 71%). MH+ 283.9.

12.2 N-(4,4′-Bithiazol-5-yl)-2-(isoquinolin-5-yl)acetamide

Conversion of tert-Butyl 4,4′-bithiazol-5-ylcarbamate to the abovetitled compound was performed according to the procedure detailed forthe synthesis of2-(isoquinolin-5-yl)-N-(4-(pyrazin-2-yl)thiazol-5-yl)acetamide. Method[4]: rt=1.22 min; ¹H NMR (d₄-McOD): δ 9.73 (s, 1H), 8.79 (d, J=2.0 Hz,1H), 8.63-8.45 (m, 4H), 8.30 (d, J=7.1 Hz, 1H), 8.09 (t, J=7.8 Hz, 1H),7.86 (d, J=2.0 Hz, 1H), 4.58 (s, 2H); MH+ 353.1.

EXAMPLE 13 Synthesis of2-(4-methoxyphenyl)-N-(2-(2-oxooxazolidin-3-yl)thiophen-3-yl)acetamide(84)

13.1. 3-(3-Nitrothiophen-2-yl)oxazolidin-2-one

Potassium tert-butoxide (1.86 g, 16.6 mmol) and oxazolidin-2-one (1.90g, 21.8 mmol) in DMF (50 ml) was stirred for 30 min.2-chloro-3-nitrothiophene (1.64 g, 10.0 mmol) was added and after 1 h,the solution was placed into a preheated oil bath at 100° C. Afterstirring for 1 h, the solution was diluted with brine and extracted withdiethyl ether. The combined organic extracts were dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas flash chromatographed with 9:1, 4:1, 7:3, 3:2, and 1:1 hexane:ethylacetate as the eluant to yield impure3-(3-nitrothiophen-2-yl)oxazolidin-2-one. Method [3] Retention time 2.50min by HPLC (MH+ 215) and (M+Na=237).

13.2. 3-(3-Aminothiophen-2-yl)oxazolidin-2-one

The title compound was prepared from3-(3-nitrothiophen-2-yl)oxazolidin-2-one according to the procedures ofExample 1.97.2. Method [7] Retention time 0.85 min by HPLC (MH+ 185).

13.3.2-(4-methoxyphenyl)-N-(2-(2-oxooxazolidin-3-yl)thiophen-3-yl)acetamide

The title compound was prepared from3-(3-aminothiophen-2-yl)oxazolidin-2-one and 2-(4-methoxyphenyl)aceticacid (510 mg, 3.06 mmol) using protocol B. The crude product waspurified by HPLC. Method [7] Retention time 2.95 min by HPLC (MH+ 333).¹H NMR (300 MHz, CDCl₃): δ 8.14 (broad s, 1H), 7.39 (d, J=5.7 Hz, 1H),7.27 (d, J=9.0 Hz, 2H), 7.06 (d, J=5.7 Hz, 1H), 6.92 (d, J=9.0 Hz, 2H),4.47 (m, 2H), 3.89 (m, 2H), 3.83 (s, 3H), 3.64 (s, 2H).

EXAMPLE 14 Determination of Kinase Activities Abbreviations

DTP: DL-dithiothreitol; DMSO: dimethyl sulfoxide, BSA: bovine serumalbumin; ATP: adenosine triphosphate; MAPK: mitogen-activated proteinkinase; EDTA: ethylenediaminetetraacetic acid; HEPES:(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid).

Materials EPIW 1

Biotin-Jun-Jun 50mer(BIOTIN-LC-Asn-Pro-Lys-Ile-Leu-Lys-Gln-Ser-Met-Thr-Leu-Asn-Len-Ala-Asp-Pro-Val-Gly-Ser-Leu-Lys-Pro-His-Leu-Arg-Ala-Lys-Asn-Ser-Asp-Leu-Leu-Thr-Ser-Pro-Asp-Val-Gly-Leu-Leu-Lys-Leu-Ala-Ser-Pro-Glu-Arg-lu-Arg-Leu-OH)

EPIG-1

Biotin-ELK-1 45mer(BIOTLN-LC-Pro-Gln-Lys-Gly-Arg-Lys-Pro-Arg-Asp-Leu-Glu-Leu-Pro-Leu-Ser-Pro-Ser-Leu-Leu-Gly-Gly-Pro-Gly-Pro-glu-Thr-Leu-Ser-Pro-Ile-Ala-Pro-Arg-Ser-Pro-Ala-Lys-Leu-Ser-Phe-Gln-Phe-Pro-Ser-Ser-OH)

EPIG-2

Biotin-ATP-2 35mer(BIOTIN-LC-Leu-Ala-Val-His-Lys-His-Lys-His-Glu-Met-Thr-Leu-Lys-Phe-Gly-Pre-Ala-Arg-Asn-Asp-Ser-Val-Ile-Val-Ala-Asp-Gln-Thr-Pro-Thr-Pro-Thr-Arg-Phe-Leu-OH)

aP38δ (Upstate Biotech); aP38δ (Cell Signaling Technology); SA-XL (Highgrade XL665-conjugated streptavidin SA-Xlent, CIS Bio International);Eu-ELK-1-Ab (Phospho-ELK-1 antibody from Cell Signaling Technologylabeled by Perkin Elmer with Lance Eu W1024); Eu-ATF-2-Ab (Phospho-ATF-2antibody from Cell Signaling Technology labeled by Perkin Elmer withLance Eu W1024); Eu-Ser-63-Ab (Phospho-c-Jun (Ser63) II antibody fromCell Signaling Technology labeled by Perkin Elmer with Lance Eu W1024);Eu-Ser-73-Ab (Phospho-c-Jun (Ser73) II antibody from Cell SignalingTechnology labeled by Perkin Elmer with Lance Eu W1024); Eu-ELK-1-Ab(Phospho-ELK-1 antibody from Cell Signaling Technology labeled by PerkinElmer with Lance Eu W1024); aJNK1/SAPK1c, aJNK2/SAPK1a, aJNK3/SAPK1b,uJNK1/SAPK1c, uJNK2/SAPK1a, uJNK3/SAPK1b, MKK4/SKK1 active, MKK7b1active, uMAPK2/Erk2, MEK1 (active), up38α/SAPK2α and MKK6/SKK3 (active)from Upstate Cell Signaling Solutions; K252a (A.G. Scientific); 506126(Calbiochem).

Reagents

Reagents were prepared and stored as specified below.

JNK Buffer Stock Solution:

-   27 mM HEPES (free acid), 1 mM MgCl₂, pH 7.0, prepared by media    kitchen and stored 4° C.

JNK Detection Buffer

-   50 mM HEPES, 0.1% BSA, 400 mM NaCl, stored at: 4° C.    0.5 M EDTA. 0.5 M EDTA in DI water, stored at RT.

1 mM ATP

-   275.6 mg of ATP (MW 551.2) were dissolved in 500 mL DI H₂O and    stored at −20° C.

4.1. Active MAPK TR-FRET Assay Procedure

-   (1) Assay buffer #1 was prepared (JNK buffer stock solution, 0.0025%    Tween, 1 mM DTT).-   (2) Assay buffer #2 was prepared (assay buffer #1, 0.025% BSA).-   (3) Test compound solution preparation: 5× compound solution was    prepared using assay buffer #1 with 5% DMSO. The compound solution    (10 μl/well) was added to a 384-well plate.-   (4) aMAPK preparation: aMAPK stock (100 ug/ml) was thawed from    −80° C. on ice, and aMAPK (10 ng/20 μl=0.5 ng/μl) solution using    assay buffer #2 was prepared. The aMAPK solution (20 μl/well) was    added to the plate. The plate was shaken and the enzyme was    incubated with the compound at RT for 10 min.-   (5) ATP/substrate solution preparation: MP and substrate stocks were    thawed on ice. 2.5× ATP/substrate, (75 μM ATP/50 nM ELK-1) was    prepared using assay buffer #1. The ATP/substrate (20 μl/well) was    added to the plate. The plate was shaken and incubated at 30° C. for    1 hr.-   (6) EDTA preparation: 30 mM EDTA was prepared using 0.5M EDTA stock    and assay buffer #1. The EDTA (10 μl/well) was added to the plate to    quench the enzyme reaction, and the plate was shaken well.-   (7) Detection reagent preparation: Eu-ELK-1-Ab and SA-XL stocks were    thawed on ice. 4× Eu-Anti-ELK-1/SA-XL (2 nM Eu-Anti-ELK-1/9.4 nM    SA-XL) using JNK detection buffer was prepared. The 4×    Eu-Anti-ELK-1/SA-XL solution (20 μl/well) was added to the plate.    The plate was shaken and incubated at RT for 1 hr before reading the    plate on LJL using ratiometric method named HTRF.

14.2. Active p38 TR-FRET Assay Procedures

-   (1) Assay buffer #1 with 0.0025% Tween and 1 mM DTT was prepared    using JNK buffer stock solution.-   (2) Assay buffer #2 with 0.025% BSA was prepared using the assay    buffer #1.-   (3) Test compound solution preparation: 5× compound solution was    prepared using assay buffer #1 with 5% DMSO. The compound solution    (10 μl/well) was added to a 384-well plate (Corning, Cat No. 3654).-   (4) aP38 preparation: aP38 stock (100 ug/ml) at 80° C. was thawed on    ice and a P38 (30 ng/20 μl=1.5 ng/μl) solution using assay buffer #2    was prepared. The P38 solution (20 μl/well) was added to the plate.    The plate was shaken and the enzyme was incubated with compound at    RT for 10 min.-   (5) ATP/substrate solution preparation: ATP and substrate stocks    were thawed on ice. 2.5× ATP/substrate (75 μM ATP/50 nM ATF-2) was    prepared using assay buffer #1. The ATP/substrate (20 μl/well) was    added to the plate, the plate was shaken, and the plate was incubate    at 30° C. for 1 hr.-   (6) EDTA preparation: 30 mM EDTA was prepared using 0.5M EDTA stock    and assay buffer #1. The EDTA (10 μl/well) was added to the plate to    quench the enzyme reaction and the plate was shaken well.-   (7) Detection reagent preparation: Eu-Anti-ATF-2 and SA-XL stocks    were thawed on ice. 4× Eu-Anti-ATF-2/SA-XL (2 nM Eu-Anti-ATF-2/9.4    nM SA-XL) was prepared using JNK detection buffer. The    Eu-Anti-ATF-2/SA-XL solution (20 μl/well) was added to the plate.    The plate was shaken and incubated at RT for 1 hr before reading the    plate on LJL using ratiometric method named HTRF.

14.3. Active JNK 1,2 and 3 TR-FRET Assay Procedures

-   (1) Assay buffer #1 with 0.0025% Tween and 1 mM DTT was prepared    using JNK buffer stock solution.-   (2) Assay buffer #2 with 0.025% BSA was prepared using the assay    buffer #1.-   (3) Test compound solution preparation: 5× compound solution was    prepared using assay buffer #1 with 5% DMSO. The compound solution    (10 μl/well) was added to a 384-well plate (Corning, Cat No. 3654).-   (4) aJNK1, 2 or 3 preparation: aJNK stock (100 μg/ml) at −80° C. was    thawed on ice and ajNK (1.6 ng/ml) solution was prepared using assay    buffer #12. The aJNK solution (20 μl/well) was added to the plate    and the plate was shaken. The enzyme was incubated with the compound    at RT for 10 min.-   (5) ATP/substrate solution preparation: ATP and substrate stocks    were thawed on ice. 2.5× ATP/substrate (e.g., 25 μM or 2.5 mM    ATP/50nM EPIW-1) was prepared using assay buffer #1. The    ATP/substrate (20 μl/well) was added to the plate and the plate was    shaken. The plate was incubated at RT for 15 min. Note: In an    exemplary assay, the final ATP concentration was about 1 mM.-   (6) EDTA preparation: 30 mM EDTA was prepared using 0.5M EDTA stock    and assay buffer #1. The EDTA (10 μl/well) was added to the plate to    quench the enzyme reaction and the plate was shaken well.-   (7) Detection reagent preparation: Eu-63 and SA-XL stocks were    thawed on ice. 4× Eu-63/SA-XL (2 nM Eu-63/9.4 nM SA-XL) was prepared    using JNK detection buffer. The Eu-63/SA-XL solution (20 μl/well)    was added to the plate and the plate was shaken. The plate was    incubated at RT for 1 hr before reading the plate on LJL using    ratiometric method named HTRF.

14.4. Coupled JNK 1,2 and 3 TR-FRET Assay Procedures

-   (1) Assay buffer with 0.0025% Tween, 0.01% BSA, and 1 mM DTT was    prepared using, JNK buffer stock solution.-   (2) Test compound solution preparation: 5× compound solution,    including EDTA background, was prepared using assay buffer with 5%    DMSO. The compound solution (1 μl/well) was added to a 384-well    plate (Corning, Cat No. 3654).-   (3) uJNK1,2, or 3 activation reaction preparation: uJNK activation    solution was prepared using assay buffer (1.6 ng/ml MKK4, 1.6 ng/ml    MKK 7, 16 ng/ml uJNK, and 20 uM ATP final). The uJNK activation    solution (35 μl/well) was added to the plate, the plate was shaken,    and the reaction mixture was incubated with compound at 30° C. for    60 min.-   (4) c-Jun substrate solution preparation: 50 nM EPIW-1, c-Jun    peptide, was prepared using assay buffer (15 nM final). The EPIW-1    solution (15 μl/well) was added to the plate, the plate was shaken    and incubated at 30° C. for 60 min.-   (5) EDTA preparation: 30 mM EDTA was prepared using 0.5M EDTA stock    and assay buffer. The EDTA (10 μl/well) was added to the plate to    quench the enzyme reaction and the plate was shaken well.-   (6) Detection reagent preparation: Eu-73 and SA-XL stocks were    thawed on ice. 4× Eu-73/SA-XL (2 nM Eu-73/9.4 nM SA-XL) were    prepared using JNK detection buffer. The Eu-73/SA-XL solution (20    μl/well) was added to the plate. The plate was shaken and incubated    at RT for 1 hr before reading the plate on LJL using ratiometric    method named HTRF.

14.5. Coupled MAPK2/Erk2 TR-FRET Assay Procedures

-   (1) Assay buffer with 0.0025% Tween, 0.01% BSA, and 1 mM DTT was    prepared using JNK buffer stock solution.-   (2) Test compound solution preparation: 5× compound solution,    including EDTA background, was prepared using assay buffer with 5%    DMSO. The compound solution (10 μl/well) was added to a 384-well    plate (Corning, Cat No. 3654).-   (3) uMAPK/Erk2 activation reaction preparation: uMAPK activation    solution was prepared using assay buffer (16 ng/ml MEK1, 160 ng/ml    uMAPK2/Erk2, and 60 uM ATP final). The uMAPK activation solution (35    μl/well) was added to the plate. The plate was shaken and the    reaction mixture was incubated with compound at 30° C. for 60 min.-   (4) ELK-1 substrate solution preparation: 50 nM ELK-1 peptide was    prepared using assay buffer (1.5 nM final). The ELK-1 peptide    solution (15 μl/well) was added to the plate. The plate was shaken    and incubated at 30° C. for 60 min.-   (5) EDTA preparation: 30 mM EDTA was prepared using 0.5M EDTA stock    and assay buffer. The EDTA (10 μl/well) was added to the plate to    quench the enzyme reaction and the plate was shaken well.-   (6) Detection reagent preparation: Eu-ELK-1-Ab and SA-XL stocks were    thawed on ice. 4× Eu-Anti-ELK-1/SA-XL (2 nM Eu-Anti-ELK-1/9.4 nM    SA-XL) was prepared using JNK detection buffer. The    Eu-Anti-ELK-1/SA-XL solution (20 μl/well) was added to the plate.    The plate was shaken and incubated at RT for 60 min. before reading    the plate on LJL using ratiometric method named HTRF.

14.6. Coupled p38α/SAPK2α TR-FRET Assay Procedures

-   (1) Assay buffer with 0.0025% Tween, 0.01% BSA, and 1 mM DTT was    prepared using JNK buffer stock solution.-   (2) Test compound solution preparation: 5× compound solution,    including EDTA background, was prepared using assay buffer with 5%    DMSO. The compound solution (10 μl/well) was added to a 384-well    plate (Corning, Cat No. 3654).-   (3) up38α/SAPK2α activation reaction preparation: up38α activation    solution was prepared using assay buffer (48 ng/ml MKK6, 480 ng/ml    up38α and 60 uM ATP final). The up38α activation solution (35    μl/well) was added to the plate. The plate was shaken and the    reaction mixture was incubated with compound at 30° C. for 60 min.-   (4) ATF-2 substrate solution preparation: 50 nM ATF-2 peptide was    prepared using assay buffer (15 nM final). The ATF-2 peptide    solution (15 μl/well) was added to the plate, the plate was shaken,    and the plate was incubate at 30° C. for 60 min.-   (5) EDTA preparation: 30 mM EDTA was prepared using 0.5M EDTA stock    and assay buffer. The EDTA (10 μl/well) was added to the plate to    quench the enzyme reaction and the plate was shaken well.-   (6) Detection reagent preparation: Eu-Anti-ATF-2 and SA-XL stocks    were thawed on ice. 4× Eu-Anti-ATF-2/SA-XL (2 nM Eu-Anti-ATF-2/9.4    nM SA-XL) was prepared using JNK detection buffer. The    Eu-Anti-ATF-2/SA-XL solution (20 μl/well) was added to the plate.    The plate was shaken and incubated at RT for 1 hr before reading the    plate on LJL using ratiometric method named HTRF.

EXAMPLE 15 Inhibition of Kainic Acid Induced Phospho-cJun Upregulationin Mice Hippocampi

Excitotoxic cell death can be induced experimentally by theadministration of kainic acid, a potent agonist of the kainate class ofglutamate receptors. Peripheral injection of kainic acid results inrecurrent seizures and degeneration of select populations of neurons inthe hippocampus. Activation of jnk is observed after kainic acidtreatment in vivo (see, e.g., Jeon S. H. et al., Experimental andMolecular Medicine 2000, 32(4): 227-230 and Kim et al., Molecules andCells 2001, 11(2): 144-150). Mice lacking the Jnk3 gene are resistant tokainic acid induced upregulation of phosphorylated c-jun (p-cjun) andhippocampal neuronal apotosis (see e.g., Yang D. D. et al., Nature 1997,389: 865-870). Phosphorylated c-jun in wildtype mice is upregulatedafter kainic acid administration and have demonstrated that thisupregulation is inhibited by certain compounds of the presentdisclosure.

Methods

Female, FVB/N mice (Taconic) were treated by oral gavage (PO) with one300 mg/kg dose ofN-(4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-isoquinolin-5-yl)acetamideor vehicle (0.9% saline) at a 5 ml/kg dose volume. Control animals weredosed with vehicle. Thirty minutes later animals were treatedinterperitoneally with 25 mg/kg of kainic acid or saline at a 10 ml/kgdose volume. Kainic acid was formulated in 0.9% saline. Four hours afterkainic acid administration animals were euthanized by carbon dioxide andwere transcardially perfused with 0.9% saline. Brains were removed, andseparated into left and right hemispheres. The hippocampus was dissectedfrom the right hemisphere, frozen on dry ice and kept at −80° C. untilused for quantitation of p-cjun levels.

Preweighed hippocampus tissues were homogenized in cold cell extractionbuffer (CEB) containing 1% Triton X-100, 0.1% SDS, 0.5% deoxycholate, 20mM Na₄P₂O₇, 2 mM Na₃VO₄, 0.1% SDS and protease inhibitors (PI, 2 mg/mLaprotinin and 1 mg/mL leupeptin) at a ratio of 9:1 CEB to wet tissueweight. Homogenized samples were analyzed using PathScan Phospho-c-Jun(Ser63) Sandwich ELISA Kit II from Cell Signaling Technology. Sampleswere diluted 1:10 in sample diluent provided in the kit. An 8-pointstandard curve was prepared by diluting a 10 ng/mL phos-c-Jun standard1:3 in 10% CEB/PI in sample diluent. Samples and standards were added at100 μL per well to prewetted ELISA plates which contain aphos-c-jun(ser63)-specific rabbit monoclonal capture antibody andincubated overnight at 4° C. The plate was then allowed to warm to roomtemperature and washed three times using TBS+0.05% Tween 20 (TTBS). Toeach well were added 100 μL of a mouse monoclonal c-Jun detectionantibody and the plate was incubated at 37° C. for 1 hour. The plate waswashed three times in TTBS, then 100 μL per well of an anti-mouse IgGHRP-linked antibody was added. The plate was incubated at 37° C. for 30minutes and was then washed three times in TTBS. To each well were added100 μL of TMB substrate and the plate was incubated for 10 minutes at37° C. Then stop solution was added. The colorimetric reaction was readusing a Molecular Devices Spectramax plate reader and sample data wascalculated from the standard curve fit to a 4-parameter function.

Results

Treatment with 300 mg/kg ofN-(4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(isoquinolin-5-yl)acetamideresulted in a statistically significant (unpaired t-test) 51% reductionof p-cjun in the hippocampus of FVB mice 4 hours after treatment withkainic acid. The results are summarized in Table 2, below.

TABLE 2 N-(4-chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(isoquinolin-5-yl)acetamide Inhibits Kainic Acid InducedPhospho-cJun Upregulation in Mice p-cJun Mean % of Group (ng/ml) SDVehicle p-Value Control 0.297 0.03 Kainic Acid 1.886 1.18 Kainic Acid +N-(4- 0.927 0.43 49.2 0.0025 chloro-3-(1H-1,2,4-triazol-5-yl)thiophen-2- yl)-2-(isoquinolin-5- yl)acetamide

What is claimed is:
 1. A compound having a structure according toFormula (I):

or a salt or solvate thereof, wherein ring A is 5-membered heteroarylcomprising a sulfur atom, wherein the heteroaryl is optionallysubstituted with 1 or 2 substituents independently chosen from alkyl,alkenyl, alkynyl, haloalkyl, heteroalkyl, C₃-C₁₀-cycloalkyl, 3- to8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN,halogen, OR¹², SR¹², NR¹²R¹³, C(O)R¹⁴, C(O)NR¹²R¹³, OC(O)NR¹²R¹³,C(O)OR¹², NR¹⁵C(O)R¹⁴, NR¹⁵C(O)OR¹², NR¹⁵C(O)NR¹²R¹³, NR¹⁵C(S)NR¹²R¹³,NR¹⁵S(O)₂R¹⁴, S(O)₂NR¹²R¹³, S(O)R¹⁴ and S(O)₂R¹⁴, wherein R¹², R¹³ andR¹⁵ are independently chosen from H, acyl, C₁-C₆alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl, or R¹² and R¹³, together with thenitrogen atom to which they are bound form a 5- to 7-memberedheterocyclic ring; and R¹⁴ is chosen from acyl, C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl; C^(a) and C^(b) arecarbon atoms, which are adjacent to each other and are part of ring A; Zis 5- or 6-membered heteroaryl, with the proviso that (i) when ring A isthiophene, then Z is not a heteroaryl chosen from benzoimidazole,thiazole, and benzothiazole; (ii) when ring A is thiazole, then Z is notbenzoimidazole; (iii) when ring A is thiophene, then Z is notsubstituted oxadiazole; and (iv) when ring A is thiophene, then Z is notpyrimidinone; R⁵ is chosen from H, acyl, C₁-C₆ alkyl, and C₃-C₆cycloalkyl; W is chosen from C₁-C₄ alkylene, wherein the alkylene isoptionally substituted with 1-4 substituents independently chosen fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, C₃-C₆-cycloalkyl, 3- to8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN,halogen, OR⁴², SR⁴², NR⁴²R⁴³, C(O)R⁴⁴, C(O)NR⁴²R⁴³, OC(O)NR⁴²R⁴³,C(O)OR⁴², NR⁴⁵C(O)R⁴⁴, NR⁴⁵C(O)OR⁴², NR⁴⁵C(O)NR⁴²R⁴², NR⁴⁵C(S)NR⁴²R⁴³,NR⁴⁵S(O)₂R⁴⁴, S(O)₂NR⁴²R⁴³, S(O)R⁴⁴, and S(O)₂R⁴⁴, wherein R⁴², R⁴³ andR⁴⁵ are members independently chosen from H, acyl, C₁-C₆-alkyl, 2- to6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈cycloalkyl and 3- to 8-membered heterocycloalkyl, wherein R⁴² and R⁴³,together with the nitrogen atom to which they are bound are optionallyjoined to form a 5- to 7-membered heterocyclic ring; and R⁴⁴ isindependently chosen from acyl, C₁-C₆-alkyl, 2- to 6-memberedheteroalkyl, aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3-to 8-membered heterocycloalkyl; Cy is chosen from cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl,heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1-6substituents independently chosen from substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, haloalkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, CN, halogen, OR⁵², SR⁵²,NR⁵²R⁵³, C(O)R⁵⁴, C(O)NR⁵²R⁵³, OC(O)NR⁵²R⁵³, C(O)OR⁵², NR⁵⁵C(O)R⁵⁴,NR⁵⁵C(O)OR⁵², NR⁵⁵C(O)NR⁵²R⁵³, NR⁵⁵C(S)NR⁵²R⁵³, NR⁵⁵S(O)₂R⁵⁴,S(O)₂NR⁵²R⁵³, S(O)R⁵⁴, and S(O)₂R⁵⁴, wherein R⁵², R⁵³and R⁵⁵ areindependently chosen from H, acyl, C₁-C₆, 2-to 6-membered heteroalkyl,aryl, 5- or 6-membered heteroaryl, C₃-C₈ cycloalkyl and 3- to 8-memberedheterocycloalkyl, wherein R⁵² and R⁵³, together with the nitrogen atomto which they are bound are optionally joined to form a 5- to 7-memberedheterocyclic ring; and R⁵² is independently chosen from acyl,C₁-C₆-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-memberedheteroaryl, C₃-C₈ cycloalkyl and 3- to 8-membered heterocycloalkyl.